Transthyretin amyloid polyneuropathy in France: A cross-sectional study with 413 patients and real-world tafamidis meglumine use (2009-2019).

OBJECTIVE: We aimed to describe characteristics of patients with ATTR variant polyneuropathy (ATTRv-PN) and ATTRv-mixed and assess the real-world use and safety profile of tafamidis meglumine 20mg. METHODS: Thirty-eight French hospitals were invited. Patient files were reviewed to identify clinical manifestations, diagnostic methods, and treatment compliance. RESULTS: Four hundred and thirteen patients (296 ATTRv-PN, 117 ATTRv-mixed) were analyzed. Patients were predominantly male (68.0%) with a mean age of 57.2±17.2 years. Interval between first symptom(s) and diagnosis was 3.4±4.3 years. First symptoms included sensory complaints (85.9%), dysautonomia (38.5%), motor deficits (26.4%), carpal tunnel syndrome (31.5%), shortness of breath (13.3%), and unexplained weight loss (16.0%). Mini-invasive accessory salivary gland or punch skin and nerve biopsies were most common, with a performance of 78.8-100%. TTR genetic sequencing, performed in all patients, revealed 31 TTR variants. Tafamidis meglumine was initiated in 156/214 (72.9%) ATTRv-PN patients at an early disease stage. Median treatment duration was 6.00 years in ATTRv-PN and 3.42 years in ATTRv-mixed patients. Tafamidis was well tolerated, with 20 adverse events likely related to study drug among the 336 patients. CONCLUSION: In France, ATTRv patients are usually identified early thanks to the national network and the help of diagnosis combining genetic testing and mini-invasive biopsies.

The art of simplicity: Water-soluble porphyrin-like carbon dots self-assemble into mesmerizing red glow.

In this new study, we present an intriguing development in the field of theranostics: the simplistic self-assembly of red-emissive amphiphilic porphyrin-like carbon dots (P-CDs). By harnessing their exceptional photophysical properties, we have revealed a strong candidate as the ideal photosensitizer (PS) for applications, particularly in the realm of imaging. Spanning a remarkable size average between 1-4 nm, these particles exhibit both highly stable and unparalleled emission characteristics between 650 and 715 nm in water in comparison to current carbon dots (CDs) available. Lastly, these CDs were fairly non-toxic when tested against normal human cell lines as well as were found to have favorable imaging capabilities in zebrafish embryo.

Advancing glioblastoma imaging: Exploring the potential of organic fluorophore-based red emissive carbon dots.

Over time, the interest in developing stable photosensitizers (PS) which both absorb and emit light in the red region (650 and 950 nm) has gained noticeable interest. Recently, carbon dots (CDs) have become the material of focus to act as a PS due to their high extinction coefficient, low cytotoxicity, and both high photo and thermal stability. In this work, a Federal and Drug Association (FDA) approved Near Infra-Red (NIR) organic fluorophore used for photo-imaging, indocyanine green (ICG), has been explored as a precursor to develop water-soluble red emissive CDs which possess red emission at 697 nm. Furthermore, our material was found to yield favorable red-imaging capabilities of glioblastoma stem-like cells (GSCs) meanwhile boasting low toxicity. Additionally with post modifications, our CDs have been found to have selectivity towards tumors over healthy tissue as well as crossing the blood-brain barrier (BBB) in zebrafish models.

Investigation into Red Emission and Its Applications: Solvatochromic N-Doped Red Emissive Carbon Dots with Solvent Polarity Sensing and Solid-State Fluorescent Nanocomposite Thin Films.

In this work, a NIR emitting dye, p-toluenesulfonate (IR-813) was explored as a model precursor to develop red emissive carbon dots (813-CD) with solvatochromic behavior with a red-shift observed with increasing solvent polarity. The 813-CDs produced had emission peaks at 610 and 698 nm, respectively, in water with blue shifts of emission as solvent polarity decreased. Subsequently, 813-CD was synthesized with increasing nitrogen content with polyethyleneimine (PEI) to elucidate the change in band gap energy. With increased nitrogen content, the CDs produced emissions as far as 776 nm. Additionally, a CD nanocomposite polyvinylpyrrolidone (PVP) film was synthesized to assess the phenomenon of solid-state fluorescence. Furthermore, the CDs were found to have electrochemical properties to be used as an additive doping agent for PVP film coatings.

Ultrasound arterial anomalies in patients exposed to nilotinib therapy for chronic myeloid leukemia.

INTRODUCTION: Patients exposed to nilotinib for chronic myeloid leukemia (CML) appear to be at risk of arterial complication. The prevalence and aspect of ultrasound asymptomatic arterial lesions are unknown. OBJECTIVE: To describe prevalence and characteristics of ultrasound arterial anomalies in patients treated with nilotinib for CML. METHODS: Patients treated with nilotinib from 2006 to 2015 in the department of the Paoli-Calmettes Institute, Marseille, were included retrospectively. A vascular ultrasound screening was carried out from 2010. The arterial lesions at the first examination were described: plaque and its echogenicity, stenosis or occlusion. A vascular arterial anomaly (VAA) was defined by the presence of a clinical and/or ultrasound anomaly. Patients with or without VAA at initial vascular examination were compared using bivariate and multivariate analysis. RESULTS: 74 patients were included (51.4% men, mean age 54.5 years); 25 patients had ultrasound arterial anomalies (33.8%). Carotid bulb was the most involved territory (44%). Arterial anomalies were: 88% plaques, 44%>50% stenosis and 12% occlusion. 72.7% plaques were echolucent or hypoechogenic. A VAA was present in 25 patients with initial vascular evaluation (33.8%). Patients with VAA at baseline were significantly older (64.9 vs 49.3, P<0.001), older at nilotinib initiation (60.8 vs 46.5, P<0.001), with more arterial hypertension (40% vs 12.2%, P=0.01), with more cardiovascular risk factors (P=0.03). In patient with no cardiovascular risk factor 12.5% had VAA (n=24). CONCLUSION: Nilotinib seems to be associated to arterial lesions of unstable lipid-like appearance. The most involved arterial territory was the carotid bulb and the most common lesion was echolucent or hypoechogenic plaque. VAA can occur in patients without cardiovascular risk factors. This result encourages us to systematically screen and follow all patients exposed to nilotinib even those without cardiovascular risk factors.

In situ revascularization with rifampicin-soaked silver polyester graft for aortic infection: Results of a retrospective monocentric series of 18 cases.

OBJECTIVE: To evaluate the short and long-term results of in situ prosthetic graft treatment using rifampicin-soaked silver polyester graft in patients with aortic infection. MATERIAL AND METHOD: All the patients surgically managed in our center for an aortic infection were retrospectively analyzed. The primary endpoint was the intra-hospital mortality, secondary outcomes were limb salvage, persistent or recurrent infection, prosthetic graft patency, and long-term survival. RESULTS: From January 2004 to December 2015, 18 consecutive patients (12 men and 6 women) were operated on for aortic infection. Six mycotic aneurysms and 12 prosthetic infections, including 8 para-entero-prosthetic fistulas, were treated. In 5 cases, surgery was performed in emergency. During the early postoperative period, we performed one major amputation and two aortic infections were persistent. Intra-hospital mortality was 27.7%. The median follow-up among the 13 surviving patients was 26 months. During follow-up, none of the 13 patients presented reinfection or bypass thrombosis. CONCLUSION: This series shows that in situ revascularization with rifampicin-soaked silver polyester graft for aortic infection have results in agreement with the literature in terms of intra-hospital mortality with a low reinfection rate.

Novel CAPN3 variant associated with an autosomal dominant calpainopathy.

AIMS: The most common autosomal recessive limb girdle muscular dystrophy is associated with the CAPN3 gene. The exclusively recessive inheritance of this disorder has been recently challenged by the description of the recurrent variants, c.643_663del21 [p.(Ser215_Gly221del)] and c.598_612del15 [p.(Phe200_Leu204del)], associated with autosomal dominant inheritance. Our objective was to confirm the existence of autosomal dominant calpainopathies. METHODS: Through our activity as one of the reference centres for genetic diagnosis of calpainopathies in France and the resulting collaborations through the French National Network for Rare Neuromuscular Diseases (FILNEMUS), we identified four families harbouring the same CAPN3 heterozygous variant with supposedly autosomal dominant inheritance. RESULTS: We identified a novel dominantly inherited CAPN3 variant, c.1333G>A [p.(Gly445Arg)] in 14 affected patients from four unrelated families. The complementary phenotypic, functional and genetic findings correlate with an autosomal dominant inheritance in these families, emphasizing the existence of this novel transmission mode for calpainopathies. The mild phenotype associated with these autosomal dominant cases widens the phenotypic spectrum of calpainopathies and should therefore be considered in clinical practice. CONCLUSIONS: We confirm the existence of autosomal dominant calpainopathies as an entity beyond the cases related to the in-frame deletions c.643_663del21 and c.598_612del15, with the identification of a novel dominantly inherited and well-documented CAPN3 missense variant, c.1333G>A [p.(Gly445Arg)]. In addition to the consequences for genetic counselling, the confirmation of an autosomal dominant transmission mode for calpainopathies underlines the importance of re-assessing other myopathies for which the inheritance is considered as strictly autosomal recessive.

Elbow Medial Ulnar Collateral Ligament chronic isolated insufficiency: anatomical M-UCL reconstruction technique and clinical experience in a mid-term follow-up.

PURPOSE: This study aims to clinically evaluate, at mid-term follow-up, a group of patients treated by the senior author in the last 6 years with our anatomical double-bundle reconstruction surgical technique for the medial ulnar collateral ligament (M-UCL) insufficiency. METHODS: In this study, we included only patients affected by chronic valgus elbow instability, diagnosed with an accurate clinical evaluation combined with an MRI, without associated fractures that had been surgically treated in the past and without additional instability detected during the first checkup and in the preoperative evaluation under anesthesia. The nine patients enrolled were operated by the senior author between 2011 and 2014 (from 16 to 49 years old at surgery, all amateur sportsmen). The average follow-up is 4 years (47.6 months). The values of the range of movement were recorded and compared. Pain assessment was performed using the VAS scoring system. The recovery of daily activities was evaluated through the validated MEPS and Quick-DASH score scales. All patients underwent an X-ray in two standard projections and a preoperative and follow-up MRI. RESULTS: The recovery of the range of motion was complete in six cases. The remaining three patients had minor loss of extension. None of the patients reported flexion deficits nor pronation-supination at follow-up. All patients achieved subjectively perceived stability and clinically objectified stability at follow-up. Five patients referred a total lack of pain at follow-up. Seven patients achieved full marks in the Mayo Elbow Performance Score and an excellent improvement in the Quick-DASH score. CONCLUSIONS: Excellent functional results indicate that M-UCL isolated reconstruction with autologous hamstrings described in this study is a reliable and replicable technique with a reduced incidence of complications. Resuming sports is consistently successful in our patients.

Eosinophilic granulomatosis with polyangiitis and laryngeal involvement: review of the literature and a cross-sectional prospective experience.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis and granulomatosis with polyangiitis show variable otorhinolaryngological involvement. Up to 14 per cent of granulomatosis with polyangiitis patients have subglottis involvement; little is known about the laryngeal involvement in eosinophilic granulomatosis with polyangiitis. METHOD: A literature review was conducted, together with a prospective cross-sectional analysis of 43 eosinophilic granulomatosis with polyangiitis patients. All patients underwent fibre-optic laryngoscopy with narrow-band imaging, and completed health-related questionnaires. RESULTS: The literature review showed only two cases of laryngeal involvement in eosinophilic granulomatosis with polyangiitis; in our cohort, no cases of subglottis stenosis were found, but local signs of laryngeal inflammation were present in 72 per cent of cases. Of the patients, 16.2 per cent had a pathological Reflux Finding Score (of 7 or higher). CONCLUSION: Laryngeal inflammation in eosinophilic granulomatosis with polyangiitis is frequent. It is possibly due more to local factors than to eosinophilic granulomatosis with polyangiitis itself. However, ENT evaluation is needed to rule out possible subglottis inflammation. These findings are in line with current literature and worthy of confirmation in larger cohorts.

Erratum to: Relationship between Clinical, MRI, and Arthroscopic Findings: A Guide to Correct Diagnosis of Meniscal Tears.

[This corrects the article DOI: 10.1055/s-0037-1605583.].

Relationship between Clinical, MRI, and Arthroscopic Findings: A Guide to Correct Diagnosis of Meniscal Tears.

Purpose The aim of this prospective study was to compare and correlate clinical, MRI, and arthroscopic findings in cases of suspected meniscal tears. Using arthroscopic findings as the gold standard, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of clinical investigation and MRI were evaluated to determine if is possible, after a careful examination, to bypass MRI and perform directly arthroscopy in suspected cases. Methods A total of 80 patients with a history of knee trauma, preoperative RX, and MRI underwent arthroscopy over an 8-month period at our department. All patients had a clinical examination performed by an experienced knee surgeon. These examiners evaluated and recorded the results of three tests: medial and lateral joint line tenderness test, McMurray's test, and Apley's test. The injury was classified as a meniscal tear if there were at least two positive tests. Finally, using the arthroscopic findings as the gold standard, sensibility, specificity, accuracy, positive and negative predictive values of clinical examination, and MRI were evaluated and compared. Results Clinical examination performed by an experienced knee surgeon reported better sensitivity (91 vs. 85%), specificity (87 vs. 75%), accuracy (90 vs. 82%), positive predictive value (94 vs. 88%), and negative predictive value (81 vs. 71%) than MRI for medial meniscal tears. These parameters showed minimal differences for lateral meniscal tears. Conclusion Clinical examination performed by an experienced knee surgeon provided equal or better results to diagnose meniscal injuries in comparison to MRI. MRI is not necessary to confirm these lesions and should not be used as the primary diagnostic tool. Level of Evidence Level II, prospective study.

Popliteal Artery Entrapment Syndrome in Children: Experience With Four Cases of Acute Ischaemia and Review of the Literature.

OBJECTIVE: Popliteal artery entrapment syndrome (PAES) is an uncommon anatomical anomaly, frequently described in adults. The most common symptom is claudication. Acute limb ischaemia (ALI) in children is rare, but it may evolve and lead to limb loss or lifelong complications. Clinical and surgical experience of PAES in children is reported. Data from the literature are analysed in order to assess the severity of this disease and to identify the factors characterising the diagnosis and the outcome of treatment in paediatric patients. METHODS: Four children (aged 7-16 years) were referred with ALI due to PAES. Among the 439 articles reporting cases of PAES, 55 patients under 18 years of age were the focus. The PAES cases were classified according to the Love and Whelan classification modified by Rich. RESULTS: Data from 79 children (106 limbs, 27 bilateral PAES) were collected and analysed. Type I PAES was present in 41 (39%), Type II in 23 (22%), Type III in 24 (23%), Type IV in 12 (11%), and Type V in two (2%) limbs. A functional PAES was present in one patient bilaterally. In two cases, the type of PAES was not reported. Claudication occurred in 68 cases (64%), and ALI in 19 (18%). In 60 cases (57%), revascularisation with or without myotomy was required; myotomy alone was performed in 41 cases (39%). CONCLUSIONS: Symptomatic PAES in children should be considered a severe condition requiring urgent investigation in order to avoid any delays in the treatment. Early diagnosis and treatment are essential to prevent serious complications. The long-term outcomes of surgical treatment with the correction of the anatomical anomaly and vascular reconstruction are satisfactory with a low complication rate.

Amplatzer Plug to Occlude the Internal Iliac Artery During Endovascular Aortic Aneurysm Repair: A Large Multicenter Study.

OBJECTIVE: During endovascular repair of abdominal aortic aneurysms (EVAR), in the absence of a distal iliac landing zone, the Amplatzer plug is increasingly being used to replace other internal iliac artery (IIA) embolization techniques. This study aimed at assessing the technical success, complication occurrence, and durability of the Amplatzer plug for IIA embolization. METHOD: From January 1, 2007 to December 31, 2013, all consecutive patients who underwent internal iliac embolization with an Amplatzer plug during EVAR were included in the study. There were 169 patients, (160 men, 9 women, mean 75 ± 9 years), treated by unilateral (158 cases, 93%) or bilateral (11 cases, 7%) embolization of the IIA, performed either separately prior to (65 cases, 38.5%) or during EVAR (104 cases, 61.5%). Follow up CT scan and/or US scan were performed 1 month after treatment and yearly thereafter. The inclusions were done retrospectively but the series was continuous and consecutive. Data were collected and analyzed using acquisition REDCap software. RESULTS: The technical success rate was 97.6%. Failures were device migration (n = 1), navigation failure (n = 2), and release outside the target zone (n = 1). On average, 1.43 plugs were required to achieve the embolization. The average amount of contrast agent for the embolization procedure was 111 ± 51 mL and the radiation dose was 127,777 ± 89,528 mGy/cm(2). The total fluoroscopy time was 854 ± 538 seconds. No re-canalization of the IIA trunk was observed during follow up. Complications were buttock claudication (n = 41, 24.3%), which resolved in 24 cases (58.5%, 24/41) at the first follow up, and intestinal ischemia requiring limited bowel resection in two cases. CONCLUSION: This multicenter study is the largest published to date. It demonstrates the efficacy and reliability of the Amplatzer plug to embolize the IIA during EVAR, with few side effects.

HCV - Estimation of the number of diagnosed patients eligible to the new anti-HCV therapies in Italy.

OBJECTIVE: The present research wants to take a picture of the current epidemiological scenario regarding HCV infection in Italy. Studies used to estimate HCV burden of illness in Italy were so far local and performed a number of years ago, not mirroring the state of the art. EpaC wanted to provide a real number of diagnosed patients, eligible to new anti-HCV therapies. PATIENTS AND METHODS: EpaC is the most important Italian NGO for hepatopathic patients. A number of sources were cross-checked. Starting from all regional data regarding HCV-related exemptions, a correction/integration was performed with online questionnaire to associated patients (from which we derived patients cured and also other/no exemptions); survey to all prescribing centers in Italy (from which we derived the percentage of ineligible patients); prevalence of particular subpopulations was also collected (prisoners and HIV/HCV coinfected); calculations of new diagnosed, dead and cured patients in 2015. Excluded patients were illegal immigrants and active drug addicts (subpopulations currently rarely cured). RESULTS: A total of 221,549 patients were derived from regional exemptions databases and the mean national prevalence was 0.364%. Adding patients without exemptions/other exemptions, total was 308,624. We deducted the yearly deaths, cured and not eligible patients and, last, integrated with coinfected and prisoner special groups. Prevalence was also estimated at regional level, highlighting a reduction of the typical North-to-South prevalence gradient. Applying the above-mentioned corrections/integrations, total diagnosed and eligible HCV patients in Italy who can be immediately cured are supposed to range 163,148-187,756. CONCLUSIONS: This is a research aimed at filling an informative gap able to provide useful actual information in terms of HCV patients real-life management and future resource allocation. These data may be considered the basis for policy- and decision-makers to plan and manage patients ready to be cured. The research does not provide information on patients not yet diagnosed.

Clinical massively parallel sequencing for the diagnosis of myopathies.

Massively parallel sequencing, otherwise known as high-throughput or next-generation sequencing, is rapidly gaining wide use in clinical practice due to possibility of simultaneous exploration of multiple genomic regions. More than 300 genes have been implicated in neuromuscular disorders, meaning that many genes need to be considered in a differential diagnosis for a patient affected with myopathy. By providing sequencing information for numerous genes at the same time, massively parallel sequencing greatly accelerates the diagnostic processes of myopathies compared to the classical "gene-after-gene" approach by Sanger sequencing. In this review, we describe multiple advantages of this powerful sequencing method for applications in myopathy diagnosis. We also outline recent studies that used this approach to discover new myopathy-causing genes and to diagnose cohorts of patients with muscular disorders. Finally, we highlight the key aspects and limitations of massively parallel sequencing that a neurologist considering this test needs to know in order to interpret the results of the test and to deal with other issues concerning the test.

Meiofauna increases bacterial denitrification in marine sediments.

Denitrification is a critical process that can alleviate the effects of excessive nitrogen availability in aquatic ecosystems subject to eutrophication. An important part of denitrification occurs in benthic systems where bioturbation by meiofauna (invertebrates <1 mm) and its effect on element cycling are still not well understood. Here we study the quantitative impact of meiofauna populations of different abundance and diversity, in the presence and absence of macrofauna, on nitrate reduction, carbon mineralization and methane fluxes. In sediments with abundant and diverse meiofauna, denitrification is double that in sediments with low meiofauna, suggesting that meiofauna bioturbation has a stimulating effect on nitrifying and denitrifying bacteria. However, high meiofauna densities in the presence of bivalves do not stimulate denitrification, while dissimilatory nitrate reduction to ammonium rate and methane efflux are significantly enhanced. We demonstrate that the ecological interactions between meio-, macrofauna and bacteria are important in regulating nitrogen cycling in soft-sediment ecosystems.

Endovascular aortic injury repair after thoracic pedicle screw placement.

Our objective was to describe the management and prevention of thoracic aortic injuries caused by a malposition of pedicle screws in corrective surgery of major spine deformities. Positioning pedicle screws in thoracic vertebras by posterior approach exposes to the risk of injury of the elements placed ahead of the thoracic spine, as the descending thoracic aorta. This complication can result in a cataclysmic bleeding, needing urgent vascular care, but it can also be totally asymptomatic, resulting in the long run in a pseudoaneurysm, justifying the systematic removal of the hardware. We report the case of a 76-year-old woman who underwent spinal correction surgery for thoraco-lumbar degenerative kypho-scoliosis. Immediately after the surgery, a thoracic aortic injury caused by the left T7 pedicle screw was diagnosed. The patient underwent a two-step surgery. The first step was realized by vascular surgeons and aimed to secure the aortic wall by short endovascular aortic grafting. During the second step, spine surgeons removed the responsible screw by posterior approach. The patient was discharged in a rehabilitation center 7 days after the second surgery. When such a complication occurs, a co-management by vascular and spine surgeons is necessary to avoid major complications. Endovascular management of this kind of vascular injuries permits to avoid an open surgery that have a great rate of morbi-mortality in frail patients. Nowadays, technologies exist to prevent this kind of event and may improve the security when positioning pedicle screws.

Nitrogen inputs to a river course in a heavily impacted watershed: a combined hydrochemical and isotopic evaluation (Oglio River Basin, N Italy).

This study aims at evaluating sources and processes affecting NO3(-) concentrations in the Oglio River. Five sampling campaigns considered the main watercourse, tributaries, point pollution sources, springs, and groundwater. Physico-chemical parameters, N forms, B, Sr(2+), stable isotopes (δ(2)HH2O, δ(18)OH2O, δ(15)NNO3, δ(18)ONO3, δ(11)B) and discharge were measured. Hydrological modelling was performed using mass balance and End Member Mixing Analysis equations. During the irrigation period, in the upstream reach, up to 90% of the natural river flow is diverted for irrigation and industrial purposes; excess water drained from agricultural fields is returned to river in the downstream reach. Results evidenced, in the middle reach, a large input of NO3(-)-rich groundwater which could be quantified using hydrological modelling. Groundwater inputs are responsible for the sharp, tenfold increase in NO3(-) in the river water, from 2.2-4.4 up to 33.5 mgL(-1), and are more evident in summer, when discharge is lower. Nevertheless, river water preserves its natural B isotopic composition, indicating that the two tracers do not have a common origin and are not co-migrant. In the lower plain, surface-groundwater interconnections and human disturbances in the water cycle favour the recycling of the compounds in the environment, and lead to a similarity in composition of the different water bodies (Oglio River, tributaries and groundwater). The long lasting agronomical practices have profoundly modified the surface-groundwater equilibrium and chemical characteristics, resulting in a highly buffered system. Infiltrating irrigation water leaches down NO3(-) which is subsequently denitrified; when returned to the Oglio River, groundwater modifies the river water composition by dilution, in the case of NO3(-), or by addition, for other constituents (e.g. Cl(-), B). The results of this study indicate that, in order to reduce the NO3(-) transport towards the Adriatic Sea, groundwater contamination should be addressed first, with expected long recovery times.