Bariatric surgery and dimethyl fumarate-induced lymphopenia in patients with multiple sclerosis.

INTRODUCTION: Lymphopenia is a known side effect of dimethyl fumarate (DMF), a disease-modifying therapy (DMT) for patients with multiple sclerosis (pwMS). A body mass index ≥ 30 kg/m2 has been identified as a protective factor; however, no data are available on lymphopenia in pwMS undergoing to weight loss due to bariatric surgery. METHODS: We described two pwMS with history of bariatric surgery who started DMF as DMT. RESULTS: The two pwMS experienced persistent lymphopenia during DMF-treatment, which was resolved after its discontinuation. CONCLUSIONS: Several mechanisms might modify DMF pharmacokinetic profiles after bariatric surgery and its bioavailability. Absolute lymphocyte count should be monitored in pwMS treated with DMF and history of bariatric surgery and weight loss.

Neonatal diagnosis of ACTA2-related disease: A case report and review of literature.

Multisystemic smooth muscle dysfunction syndrome (MSMDS, OMIM # 613834) is a rare autosomal dominant condition caused by pathogenetic variants of ACTA2 gene that result in impaired muscle contraction. MSMDS is characterized by an increased susceptibility to aneurismal dilatations and dissections, patent ductus arteriosus, early onset coronary artery disease, congenital mydriasis, chronic interstitial lung disease, hypoperistalsis, hydrops of gall bladder, and hypotonic bladder. Here, we report an early diagnosis of a MSMDS related to ACTA2 p.Arg179His (R179H) mutation in a newborn and performed a review of the literature. An early diagnosis of MSMDS is extremely important, because of the severe involvement of cardiovascular system in the MSMDS. Multidisciplinary care and surveillance and timely management of symptoms are important to reduce the risk of complications.

Symptomatic COVID-19 course and outcomes after three mRNA vaccine doses in multiple sclerosis patients treated with high-efficacy DMTs.

BACKGROUND: Little is known about COVID-19 course and outcomes after a third booster dose of mRNA vaccine against SARS-CoV-2 (mRNA-Vax) in patients with multiple sclerosis (pwMS) treated with ocrelizumab (OCR) and fingolimod (FNG), which showed a weakened immune response to mRNA-vax. OBJECTIVES: The aim of this study was to evaluate COVID-19 course and outcomes in pwMS on OCR and FNG after receiving the third dose of mRNA-Vax and to compare it with pwMS on natalizumab (NTZ). METHODS: Inclusion criteria: >18 years of age, being treated with OCR/FNG/NTZ since the first mRNA-Vax dose; COVID-19 after a third booster dose of mRNA-Vax; no steroids use. RESULTS: Overall, 290 pwMS (79 NTZ, 126 OCR, and 85 FNG) from 17 Italian MS centers were included. Age, Expanded Disability Status Scale (EDSS) score, MS phenotype, disease, and treatment duration were significantly different across groups. PwMS who had COVID-19 on OCR and FNG compared with those on NTZ were slightly more symptomatic with higher hospitalization rates (11.1% vs 7.1% vs 1.3%, respectively). Regression models showed that the majority of the differences observed were not related to the disease-modifying treatments (DMTs) used. No fatal cases were observed. CONCLUSION: Our results support the effectiveness of the third booster dose of mRNA-Vax against severe forms of COVID-19 in pwMS treated with OCR and FNG.

Crystallographic-Morphological Connections in Star Shaped Metal-Organic Frameworks.

The symmetry of a crystal's morphology usually reflects the symmetry of the crystallographic packing. For single crystals, the space and point groups allow only a limited number of mathematical descriptions of the morphology (forms), all of which are convex polyhedrons. In contrast, concave polyhedrons are a hallmark of twinning and polycrystallinity and are typically inconsistent with single crystallinity. Here we report a new type of structure: a concave polyhedron shape single crystal having a multidomain appearance and a rare space group (P622). Despite these unusual structural features, the hexagonal symmetry is revealed at the morphological levels.

Chiral Motifs in Highly Interpenetrated Metal-Organic Frameworks Formed from Achiral Tetrahedral Ligands.

Formation of highly interpenetrated frameworks is demonstrated. An interesting observation is the presence of very large adamantane-shaped cages in a single network, making these crystals new entries in the collection of diamondoid-type metal-organic frameworks (MOFs). The frameworks were constructed by assembling tetrahedral pyridine ligands and copper dichloride. Currently, the networks' degree of interpenetration is among the highest reported and increases when the size of the ligand is increased. Highly interpenetrated frameworks typically have low surface contact areas. In contrast, in our systems, the voids take up to 63 % of the unit cell volume. The MOFs have chiral features but are formed from achiral components. The chirality is manifested by the coordination chemistry around the metal center, the structure of the helicoidal channels, and the motifs of the individual networks. Channels of both handednesses are present within the unit cells. This phenomenon shapes the walls of the channels, which are composed of 10, 16, or 32 chains correlated with the degree of interpenetration 10-, 16-, and 32-fold, respectively. By changing the distance between the center of the ligand and the coordination moieties, we succeeded in tuning the diameter of the channels. Relatively large channels were formed, having diameters up to 31.0 Å×14.8 Å.

Directing the Morphology, Packing, and Properties of Chiral Metal-Organic Frameworks by Cation Exchange.

We show that metal-organic frameworks, based on tetrahedral pyridyl ligands, can be used as a morphological and structural template to form a series of isostructural crystals having different metal ions and properties. An iterative crystal-to-crystal conversion has been demonstrated by consecutive cation exchanges. The primary manganese-based crystals are characterized by an uncommon space group (P622). The packing includes chiral channels that can mediate the cation exchange, as indicated by energy-dispersive X-ray spectroscopy on microtome-sectioned crystals. The observed cation exchange is in excellent agreement with the Irving-Williams series (MnZn) associated with the relative stability of the resulting coordination nodes. Furthermore, we demonstrate how the metal cation controls the optical and magnetic properties. The crystals maintain their morphology, allowing a quantitative comparison of their properties at both the ensemble and single-crystal level.

Defining the course of tumefactive multiple sclerosis: A large retrospective multicentre study.

BACKGROUND AND PURPOSE: Tumefactive multiple sclerosis (TuMS) (i.e., MS onset presenting with tumefactive demyelinating lesions [TDLs]) is a diagnostic and therapeutic challenge. We performed a multicentre retrospective study to describe the clinical characteristics and the prognostic factors of TuMS. METHODS: One hundred two TuMS patients were included in this retrospective study. Demographic, clinical, magnetic resonance imaging (MRI), laboratory data and treatment choices were collected. RESULTS: TuMS was found to affect women more than men (female:male: 2.4), with a young adulthood onset (median age: 29.5 years, range: 11-68 years, interquartile range [IQR]: 38 years). At onset, 52% of TuMS patients presented with the involvement of more than one functional system and 24.5% of them with multiple TDLs. TDLs most frequently presented with an infiltrative MRI pattern (38.7%). Cerebrospinal fluid immunoglobulin G oligoclonal bands were often demonstrated (76.6%). In 25.3% of the cases, more than one acute-phase treatment was administered, and almost one-half of the patients (46.6%) were treated with high-efficacy treatments. After a median follow-up of 2.3 years (range: 0.1-10.7 years, IQR: 3.4 years), the median Expanded Disability Status Scale (EDSS) score was 1.5 (range: 0-7, IQR: 2). Independent risk factors for reaching an EDSS score ≥3 were a higher age at onset (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.03-1.14, p < 0.01), a higher number of TDLs (OR: 1.67, 95% CI: 1.02-2.74, p < 0.05) and the presence of infiltrative TDLs (OR: 3.34, 95% CI: 1.18-9.5, p < 0.001) at baseline. CONCLUSIONS: The management of TuMS might be challenging because of its peculiar characteristics. Large prospective studies could help to define the clinical characteristics and the best treatment algorithms for people with TuMS.

Watershed subarachnoid hemorrhage after middle cerebral artery rescue stenting in patients with acute ischemic stroke.

Cortical subarachnoid hemorrhage is an infrequent subtype of non-aneurysmal subarachnoid hemorrhage, rarely reported in watershed territories (wSAH) after carotid stenting. It has never been reported after treatment of middle cerebral artery stenosis (MCAS) that is increasingly used in selected patients, as rescue treatment of failed mechanical thrombectomy, due to recent advancements in endovascular interventions. We present a series of patients with MCAS that developed a wSAH after stenting.

One-Year Follow-Up in Children with Conductive Hearing Loss Using ADHEAR.

BACKGROUND: The ADHEAR™ system (MED-EL, Innsbruck, Austria) is a nonsurgical bone conduction device (BCD) to treat conductive hearing loss (CHL) and single-sided deafness. In contrast to the nonsurgical alternatives on headbands or spectacle frames, the audio processor of ADHEAR is placed retroauricularly on an adhesive adapter. The published evidence on the performance of this system is limited to studies with a trial period of 2-8 weeks. OBJECTIVE: This study assesses audiological and subjective outcomes over a period of 12 months, on patients with congenital aural atresia (CAA) using the ADHEAR hearing system. METHOD: Fifteen children (mean age: 9.4 ± 4 years; range: 5-16 years) diagnosed with CAA (7 uni/8 bilateral) were included in this prospective, observational, repeated-measures study. Each subject used ADHEAR for 1 year, and the performance was evaluated after 1, 6, and 12 months. Free-field audiometry and speech discrimination tests were performed, and hearing-, general health- and device-specific questionnaires were used. RESULTS: The unaided sound field threshold improved from an average PTA4 of 63.6 ± 3.4 dB HL to an aided average PTA4 of 29.3 ± 3.0 dB HL after 1 month of device use. The word recognition score (WRS) improved from an average of 27.9 ± 15.9% unaided to an aided average WRS of 91.3 ± 4.4% (p = 0.0003) after 1 month, 92.0 ± 4.1% (p = 0.0002) after 6 months, and 92.7 ± 5.3% (p < 0.0001) after 12 months using the ADHEAR system compared to the unaided condition for all 3 time points. The improvements in the speech in noise at 1, 6, and 12 months were as well consistent over time. The average improvement at the signal to noise ratio (SNR) of +5 dB was 58% and 53% at the SNR of +0 dB. No complications were reported, and all patients continued to use the ADHEAR after the study end. The questionnaire results revealed high user satisfaction and an average wearing time of 12 h per day. CONCLUSION: This 12-month trial of the nonsurgical adhesive BCD in CAA patients showed sufficient and reliable audiological and subjective outcomes, long wearing time, and high acceptance. The ADHEAR can be considered a suitable option to treat children with CAA for the given indication, without the drawbacks of nonsurgical devices that use pressure for retention of the audio processor or the costs and possible complications involved with a surgical alternative.

Physiology and Physical Chemistry of Bile Acids.

Bile acids (BAs) are facial amphiphiles synthesized in the body of all vertebrates. They undergo the enterohepatic circulation: they are produced in the liver, stored in the gallbladder, released in the intestine, taken into the bloodstream and lastly re-absorbed in the liver. During this pathway, BAs are modified in their molecular structure by the action of enzymes and bacteria. Such transformations allow them to acquire the chemical-physical properties needed for fulling several activities including metabolic regulation, antimicrobial functions and solubilization of lipids in digestion. The versatility of BAs in the physiological functions has inspired their use in many bio-applications, making them important tools for active molecule delivery, metabolic disease treatments and emulsification processes in food and drug industries. Moreover, moving over the borders of the biological field, BAs have been largely investigated as building blocks for the construction of supramolecular aggregates having peculiar structural, mechanical, chemical and optical properties. The review starts with a biological analysis of the BAs functions before progressively switching to a general overview of BAs in pharmacology and medicine applications. Lastly the focus moves to the BAs use in material science.

Bile Salts: Natural Surfactants and Precursors of a Broad Family of Complex Amphiphiles.

Bile salts (BSs) are naturally occurring rigid surfactants with a steroidal skeleton and specific self-assembly and interface behaviors. Using bile salts as precursors, derivatives can be synthesized to obtain molecules with specific functionalities and amphiphilic structure. Modifications on single molecules are normally performed by substituting the least-hindered hydroxyl group on carbon C-3 of the steroidal A ring or at the end of the lateral chain. This leads to monosteroidal rigid building blocks that are often able to self-organize into 1D structures such as tubules, twisted ribbons, and fibrils with helical supramolecular packing. Tubular aggregates are of particular interest, and they are characterized by cross-section inner diameters spanning a wide range of values (3-500 nm). They can form through appealing pH- or temperature-responsive aggregation and in mixtures of bile salt derivatives to provide mixed tubules with tunable charge and size. Other derivatives can be prepared by covalently linking two or more bile salt molecules to provide complex systems such as oligomers, dendrimers, and polymeric materials. The unconventional amphiphilic molecular structure imparts specific features to BSs and derivatives that can be exploited in the formulation of capsules, drug carriers, dispersants, and templates for the synthesis of nanomaterials.

Metal-Coordination-Induced Fusion Creates Hollow Crystalline Molecular Superstructures.

In this work, we report the formation of superstructures assembled from organic tubular crystals mediated by metal-coordination chemistry. This template-free process involves the crystallization of molecules into crystals having a rectangular and uniform morphology, which then go on to fuse together into multibranched superstructures. The initially hollow and organic crystals are obtained under solvothermal conditions in the presence of a copper salt, whereas the superstructures are subsequently formed by aging the reaction mixture at room temperature. The mild thermodynamic conditions and the favorable kinetics of this unique self-assembly process allowed us to ex-situ monitor the superstructure formation by electron microscopy, highlighting a pivotal and unusual role for copper ions in their formation and stabilization.

Bile acid derivative-based catanionic mixtures: versatile tools for superficial charge modulation of supramolecular lamellae and nanotubes.

Self-assembled structures formed by mixtures of cationic and anionic surfactants are interesting tools for applications requiring interactions with charged particles and molecules. Nevertheless, they present instability close to the equimolar composition and poor morphological versatility, which is generally restricted to vesicles and micelles. Against this general trend, we report on bile salt derivative based catanionic mixtures assembling in tubules and lamellae depending on the mixture composition. Electrophoretic mobility measurements prove that the composition also dictates their superficial charge, which can be tuned from negative to positive by increasing the positively charged surfactant fraction in the mixtures. The study of the catanionic aggregates was conducted by means of microscopy and spectroscopy techniques and compared to the self-assembly behaviors of the individual building blocks. This study broadens the so far small array of bile salt derivative catanionic systems, confirming their distinctive behavior in the spectrum of catanionic mixtures.

Towards a Unified Testing Framework for Single-Sided Deafness Studies: A Consensus Paper.

BACKGROUND: While hearing aids for a contralateral routing of signals (CROS-HA) and bone conduction devices have been the traditional treatment for single-sided deafness (SSD) and asymmetric hearing loss (AHL), in recent years, cochlear implants (CIs) have increasingly become a viable treatment choice, particularly in countries where regulatory approval and reimbursement schemes are in place. Part of the reason for this shift is that the CI is the only device capable of restoring bilateral input to the auditory system and hence of possibly reinstating binaural hearing. Although several studies have independently shown that the CI is a safe and effective treatment for SSD and AHL, clinical outcome measures in those studies and across CI centers vary greatly. Only with a consistent use of defined and agreed-upon outcome measures across centers can high-level evidence be generated to assess the safety and efficacy of CIs and alternative treatments in recipients with SSD and AHL. METHODS: This paper presents a comparative study design and minimum outcome measures for the assessment of current treatment options in patients with SSD/AHL. The protocol was developed, discussed, and eventually agreed upon by expert panels that convened at the 2015 APSCI conference in Beijing, China, and at the CI 2016 conference in Toronto, Canada. RESULTS: A longitudinal study design comparing CROS-HA, BCD, and CI treatments is proposed. The recommended outcome measures include (1) speech in noise testing, using the same set of 3 spatial configurations to compare binaural benefits such as summation, squelch, and head shadow across devices; (2) localization testing, using stimuli that rove in both level and spectral content; (3) questionnaires to collect quality of life measures and the frequency of device use; and (4) questionnaires for assessing the impact of tinnitus before and after treatment, if applicable. CONCLUSION: A protocol for the assessment of treatment options and outcomes in recipients with SSD and AHL is presented. The proposed set of minimum outcome measures aims at harmonizing assessment methods across centers and thus at generating a growing body of high-level evidence for those treatment options.

Extracranial Venous Drainage Pattern in Multiple Sclerosis and Healthy Controls: Application of the 2011 Diagnostic Criteria for Chronic Cerebrospinal Venous Insufficiency.

The etiology of multiple sclerosis (MS) is still largely unknown and it has been proposed that an impaired venous drainage from the central nervous system, defined as chronic cerebrospinal venous insufficiency (CCSVI), may play a role in this. We investigated the prevalence of extracranial venous drainage pattern alterations in a cohort of MS patients based on the 2011 revised diagnostic criteria for CCSVI. Thirty-nine MS patients and 18 healthy subjects underwent blinded extra-cranial venous echo-color Doppler sonography to reveal the presence of CCSVI. There was no statistically significant difference between MS patients and healthy controls regarding CCSVI prevalence (p value = 0.53). The results challenge the hypothesis that CCSVI plays a primary role in the pathogenesis of MS.

Tailoring supramolecular nanotubes by bile salt based surfactant mixtures.

An approach for tailoring self-assembled tubular structures is described. By controlling the relative composition of a two-component surfactant mixture comprising the natural bile salt lithocholate and its bolamphiphilic derivative, it was possible to finely tune the nanotube cross-section of the mixed tubular aggregates that self-associated spontaneously in aqueous solution at pH 12. The diameter was found to vary up to 50% when the stoichiometric ratio of the two bile salts was changed. The tuning of supramolecular nanochannels with such remarkable precision is of significant interest for technological applications of these materials.

On the self-assembly of a tryptophan labeled deoxycholic acid.

Self-assembly of peptides and bile acids has been widely investigated because of their biological role and their potential as a tool for the preparation of nanostructured biomaterials. We herein report both the synthesis and the self-association behavior of a compound that combines the aggregation properties of bile acid- and amino acid-based molecules. The derivative has been prepared by introducing a L-tryptophan residue into the C-3 position of the deoxycholic acid skeleton and resulted in an amphoteric fluorescent labeled bile acid that shows a pH-dependent self-assembly. Under alkaline conditions it assembles into 28 nm diameter tubules, thus showing a completely different behavior compared to the precursor bile acid, which forms micelles under similar conditions. Upon heating the tubules break and turn into micelles, leading to an increase in the exposure to water of the tryptophan residue. On the other hand, in acidic solutions it aggregates into elongated micelles that further self-assemble forming a gel network, when an electrolyte is added.

Active Bone Conduction Implant and Adhesive Bone Conduction Device: A Comparison of Audiological Performance and Subjective Satisfaction.

Introduction Atresia of the external auditory canal affects 1 in every 10 thousand to 20 thousand live births, with a much higher prevalence in Latin America, at 5 to 21 out of every 10 thousand newborns. The treatment involves esthetic and functional aspects. Regarding the functional treatment, there are surgical and nonsurgical alternatives like spectacle frames and rigid and softband systems. Active transcutaneous bone conduction implants (BCIs) achieve good sound transmission and directly stimulate the bone. Objective To assess the audiological performance and subjective satisfaction of children implanted with an active transcutaneous BCI for more than one year and to compare the outcomes with a nonsurgical adhesive bone conduction device (aBCD) in the same users. Methods The present is a prospective, multicentric study. The audiological performance was evaluated at 1, 6, and 12 months postactivation, and after a 1-month trial with the nonsurgical device. Results Ten patients completed all tests. The 4-frequency pure-tone average (4PTA) in the unaided condition was of 65 dB HL, which improved significantly to 20 dB HL after using the BCI for 12 months. The speech recognition in quiet in the unaided condition was of 33% on average, which improved significantly, to 99% with the BCI, and to 91% with the aBCD. Conclusion The aBCD demonstrated sufficient hearing improvement and subjective satisfaction; thus, it is a good solution for hearing rehabilitation if surgery is not desired or not possible. If surgery is an option, the BCI is the superior device in terms of hearing outcomes, particularly background noise and subjective satisfaction.

NEDA-3 achievement in early highly active relapsing remitting multiple sclerosis patients treated with Ocrelizumab or Natalizumab.

BACKGROUND: in the early stages of Multiple Sclerosis (MS), initiating high-efficacy disease-modifying therapy (HE DMTs) may represent an optimal strategy for delaying neurological damage and long-term disease progression, especially in highly active MS patients (HAMS). Natalizumab (NAT) and Ocrelizumab (OCR) are recognized as HE DMTs with significant anti-inflammatory effects. This study investigates NEDA-3 achievement in treatment-naïve HAMS patients receiving NAT or OCR over three years. METHODS: we retrospectively enrolled treatment-naïve HAMS patients undergoing NAT or OCR, collecting demographic, clinical, and instrumental data before and after treatment initiation to compare with propensity score analysis disease activity, time to disability worsening, and NEDA-3 achievement. RESULTS: we recruited 281 HAMS patients with a mean age of 32.7 years (SD 10.33), treated with NAT (157) or OCR (124). After three years, the Kaplan-Meier probability of achieving NEDA-3 was 66.0 % (95 % CI: 57.3 % - 76.0 %) with OCR and 68.2 % (95 % CI: 59.9 % - 77.7 %) with NAT without significant differences between the two groups (p = 0.27) DISCUSSION AND CONCLUSION: starting HE DMT with monoclonal antibodies for HAMS could achieve NEDA-3 in a high percentage of patients without differences between NAT or OCR.

The role of ethnicity and native-country income in multiple sclerosis: the Italian multicentre study (MS-MigIT).

OBJECTIVE: Multiple sclerosis (MS) is a complex disorder in which environmental and genetic factors interact modifying disease risk and course. This multicentre, case-control study involving 18 Italian MS Centres investigated MS course by ethnicity and native-country economic status in foreign-born patients living in Italy. METHODS: We identified 457 MS patients who migrated to Italy and 893 age- and sex-matched native-born Italian patients. In our population, 1225 (93.2%) subjects were White Europeans and White Northern Americans (WENA) and 89 (6.8%) patients were from other ethnical groups (OEG); 1109 (82.1%) patients were born in a high-income (HI) Country and 241 (17.9%) in a low-middle-income (LMI) Country. Medical records and patients interviews were used to collect demographic and disease data. RESULTS: We included 1350 individuals (973 women and 377 men); mean (SD) age was 45.0 (11.7) years. At onset, 25.45% OEG patients vs 12.47% WENA (p = 0.039) had > 3 STIR spine lesions. At recruitment, the same group featured mean (SD) EDSS score of 2.85 (2.23) vs 2.64 (2.28) (p = 0.044) reached in 8.9 (9.0) vs 12.0 (9.0) years (p = 0.018) and underwent 1.10 (4.44) vs. 0.99 (0.40) annual MRI examinations (p = 0.035). At disease onset, patients from LMI countries had higher EDSS score than HI patients (2.40 (1.43) vs 1.99 (1.17); p = 0.032). DISCUSSION: Our results suggested that both ethnicity and socio-economic status of native country shape MS presentation and course and should be considered for an appropriate management of patients. To the best of our knowledge, this is the first study reporting on the impact of ethnicity in MS at an individual level and beyond an ecological population-perspective.