The Effect of Therapeutic Exercise and Local Cryotherapy on Lower Limb Enthesitis in Non-Radiographic Axial Spondyloarthritis: A Case Report.

BACKGROUND: Enthesitis is a common feature of spondyloarthritis and can severely impair the patient's quality of life. International guidelines recommend multidisciplinary management of this condition, combining physical and pharmacological interventions. In this case report, we demonstrate clinical and ultrasonographic improvements by prescribing local cryotherapy and therapeutic exercise alone in an adult woman with non-radiographic axial SpA (nRX-AxSpA) complaining of heel enthesitis. METHODOLOGY: A personalized program was prescribed that focused on reducing pain, joint stiffness, and muscle tightness, improving strength and endurance. Pain, function, and degree of disability were assessed using the Numerical Rating Scale, the Victorian Institute of Sport Assessment-Achilles, the single-leg heel lift test, and the Foot Function Index. In addition, lower limb muscle strength was measured using a dynamometer and enthesitis was assessed ultrasonographically using the Glasgow Ultrasound Enthesitis Score System. RESULTS: Benefits were evident as early as week 5 and persisted at 3 months on ultrasound assessment. No side effects were reported. DISCUSSION: To the best of our knowledge, this is the first report of prescribing such a strategy in a patient with nRX-AxSpA. Given the good tolerability, this intervention could be considered in patients with contraindications to pharmacologic approaches.

Elotuzumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: Extended follow-up of a multicenter, retrospective real-world experience with 321 cases outside of controlled clinical trials.

The ELOQUENT-3 trial demonstrated the superiority of the combination of elotuzumab, pomalidomide, and dexamethasone (EloPd) in terms of efficacy and safety, compared to Pd in relapsed/refractory multiple myeloma (RRMM), who had received at least two prior therapies, including lenalidomide and a proteasome inhibitor. The present study is an 18-month follow-up update of a previously published Italian real-life RRMM cohort of patients treated with EloPd. This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. After a median follow-up of 17.7 months, 213 patients (66.4%) experienced disease progression or died. Median progression-free survival (PFS) and overall survival (OS) were 7.5 and 19.2 months, respectively. The updated multivariate analysis showed a significant reduction of PFS benefit magnitude both in advanced International Staging System (ISS) (II and III) stages and previous exposure to daratumumab cases. Instead, advanced ISS (II and III) stages and more than 2 previous lines of therapy maintained an independent prognostic impact on OS. Major adverse events included grade three-fourths neutropenia (24.9%), anemia (13.4%), lymphocytopenia (15.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 19.3% and 8.7%, respectively. A slight increase in the incidence of neutropenia and lymphocytopenia was registered with longer follow-up. In conclusion, our real-world study still confirms that EloPd is a safe and possible therapeutic choice for RRMM. Nevertheless, novel strategies are desirable for those patients exposed to daratumumab.

Outcome of atypical hemolytic uremic syndrome: role of triggers and complement abnormalities in the response to C5 inhibition.

BACKGROUND: Atypical-hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy often due to uncontrolled complement activation, characterized by high risk of end-stage kidney disease (ESKD). Eculizumab has improved the outcome, however, its efficacy varies among patients and its discontinuation is debated. METHODS: To identify characteristics associated with treatment response, we analyzed 244 aHUS patients referred to our center. Patients were classified according to the presence/absence of complement abnormalities and/or triggers at onset in 4 categories: (1) primary (complement abnormality without trigger), (2) secondary (trigger without complement abnormality), (3) combined (trigger and complement abnormality), (4) idiopathic (no trigger, no complement abnormality). Response to treatment was evaluated by comparing the response to eculizumab with that of conventional therapy. Short- and long-term outcomes were evaluated with the relapse rate after discontinuation of C5-inhibition. RESULTS: Patients had a better outcome with eculizumab compared to conventional treatment, with a response rate of 81.9% vs 56.9%, p < 0.001 and a long-term cumulative incidence of ESKD of 5.8% vs 22.5% (hazard ratio 0.25, 95% confidence interval: 0.10-0.80). The excellent global response was driven by the primary and combined groups (89.8% vs 54.0% and 89.3% vs 54.2%, respectively). The relapse rate following discontinuation of the C5-inhibitor was as high as 66.7% in the primary group, 18.7% in the combined, and 0% in the secondary and idiopathic groups. CONCLUSIONS: Our data show a better outcome in aHUS patients treated with C5-inhibition, particularly in the primary and combined forms, which have a high risk of relapse after discontinuation that is not observed in the secondary and idiopathic forms.

Elotuzumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: a multicenter, retrospective, real-world experience with 200 cases outside of controlled clinical trials.

In the ELOQUENT-3 trial, the combination of elotuzumab, pomalidomide and dexamethasone (EloPd) proved to have a superior clinical benefit over pomalidomide and dexamethasone with a manageable toxicity profile, leading to its approval for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. We report here a real-world experience of 200 cases of RRMM treated with EloPd in 35 Italian centers outside of clinical trials. In our dataset, the median number of prior lines of therapy was two, with 51% of cases undergoing autologous stem cell transplant and 73% having been exposed to daratumumab. After a median follow-up of 9 months, 126 patients had stopped EloPd, most of them (88.9%) because of disease progression. The overall response rate was 55.4%, a finding in line with the pivotal trial results. Regarding adverse events, the toxicity profile in our cohort was similar to that in the ELOQUENT-3 trial, with no significant differences between younger (<70 years) and older patients. The median progression-free survival was 7 months, which was shorter than that observed in ELOQUENT-3, probably because of the different clinical characteristics of the two cohorts. Interestingly, International Staging System stage III disease was associated with worse progression-free survival (hazard ratio=2.55). Finally, the median overall survival of our series was shorter than that observed in the ELOQUENT-3 trial (17.5 vs. 29.8 months). In conclusion, our real-world study confirms that EloPd is a safe and possible therapeutic choice for patients with RRMM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

Osteoimmunology of Spondyloarthritis.

The mechanisms underlying the development of bone damage in the context of spondyloarthritis (SpA) are not completely understood. To date, a considerable amount of evidence indicates that several developmental pathways are crucially involved in osteoimmunology. The present review explores the biological mechanisms underlying the relationship between inflammatory dysregulation, structural progression, and osteoporosis in this diverse family of conditions. We summarize the current knowledge of bone biology and balance and the foundations of bone regulation, including bone morphogenetic protein, the Wnt pathway, and Hedgehog signaling, as well as the role of cytokines in the development of bone damage in SpA. Other areas surveyed include the pathobiology of bone damage and systemic bone loss (osteoporosis) in SpA and the effects of pharmacological treatment on focal bone damage. Lastly, we present data relative to a survey of bone metabolic assessment in SpA from Italian bone specialist rheumatology centers. The results confirm that most of the attention to bone health is given to postmenopausal subjects and that the aspect of metabolic bone health may still be underrepresented. In our opinion, it may be the time for a call to action to increase the interest in and focus on the diagnosis and management of SpA.

A novel array of real-time RT-PCR assays for the rapid pathotyping of type I avian paramyxovirus (APMV-1).

Newcastle disease (ND) caused by virulent avian paramyxovirus type I (APMV-1) is a WOAH and EU listed disease affecting poultry worldwide. ND exhibits different clinical manifestations that may either be neurological, respiratory and/or gastrointestinal, accompanied by high mortality. In contrast, mild or subclinical forms are generally caused by lentogenic APMV-1 and are not subject to notification. The rapid discrimination of virulent and avirulent viruses is paramount to limit the spread of virulent APMV-1. The appropriateness of molecular methods for APMV-1 pathotyping is often hampered by the high genetic variability of these viruses that affects sensitivity and inclusivity. This work presents a new array of real-time RT-PCR (RT-qPCR) assays that enable the identification of virulent and avirulent viruses in dual mode, i.e., through pathotype-specific probes and subsequent Sanger sequencing of the amplification product. Validation was performed according to the WOAH recommendations. Performance indicators on sensitivity, specificity, repeatability and reproducibility yielded favourable results. Reproducibility highlighted the need for assays optimization whenever major changes are made to the procedure. Overall, the new RT-qPCRs showed its ability to detect and pathotype all tested APMV-1 genotypes and its suitability for routine use in clinical samples.

Cardiovascular Risk Factors and Events in Fibromyalgia Patients.

BACKGROUND: Several studies have shown that patients with fibromyalgia present with neuroendocrine, inflammatory, and coagulation features linked to cardiovascular disease development. However, the exact profile of cardiovascular risk factors and events in fibromyalgia remains to be defined. OBJECTIVES: To compare the profile of cardiovascular risk factors and events between fibromyalgia outpatients and the general population in Italy. METHODS: Cardiovascular risk factors and events in fibromyalgia females were collected using the criteria adopted in the CUORE Project. RESULTS: The study comprised 62 female fibromyalgia patients and 4093 female controls from 35 to 75 years of age. The prevalence of hypertension, diabetes, atrial fibrillation, transient ischemic attack, and cardiovascular total burden was significantly higher in fibromyalgia females than in the general Italian population. No difference was found in blood fasting glucose, triglycerides, total and fractionated cholesterol levels, body mass index, and metabolic syndrome (MetS). The MetS rate was underestimated for methodological aspects. CONCLUSIONS: Fibromyalgia is associated with an increased cardiovascular burden, probably through a specific risk factor profile.

Redesign and Validation of a Real-Time RT-PCR to Improve Surveillance for Avian Influenza Viruses of the H9 Subtype.

Avian influenza viruses of the H9 subtype cause significant losses to poultry production in endemic regions of Asia, Africa and the Middle East and pose a risk to human health. The availability of reliable and updated diagnostic tools for H9 surveillance is thus paramount to ensure the prompt identification of this subtype. The genetic variability of H9 represents a challenge for molecular-based diagnostic methods and was the cause for suboptimal detection and false negatives during routine diagnostic monitoring. Starting from a dataset of sequences related to viruses of different origins and clades (Y439, Y280, G1), a bioinformatics workflow was optimized to extract relevant sequence data preparatory for oligonucleotides design. Analytical and diagnostic performances were assessed according to the OIE standards. To facilitate assay deployment, amplification conditions were optimized with different nucleic extraction systems and amplification kits. Performance of the new real-time RT-PCR was also evaluated in comparison to existing H9-detection methods, highlighting a significant improvement of sensitivity and inclusivity, in particular for G1 viruses. Data obtained suggest that the new assay has the potential to be employed under different settings and geographic areas for a sensitive detection of H9 viruses.

SARS-CoV-2 intra-host evolution during prolonged infection in an immunocompromised patient.

OBJECTIVES: Intra-host SARS-CoV-2 evolution during chronic infection in immunocompromised hosts has been suggested as being the possible trigger of the emergence of new variants. METHODS: Using a deep sequencing approach, we investigated the SARS-CoV-2 intra-host genetic evolution in a patient with HIV over a period of 109 days. RESULTS: Sequencing of nasopharyngeal swabs at three time points demonstrated dynamic changes in the viral population, with the emergence of 26 amino acid mutations and two deletions, 57% of them in the Spike protein. Such a combination of mutations has never been observed in other SARS-CoV-2 lineages detected so far. CONCLUSION: Our data confirm that persistent infection in certain immunocompromised individuals for a long time may favor the dangerous emergence of new SARS-CoV-2 variants with immune evasion properties.

First-line therapy with either bortezomib-melphalan-prednisone or lenalidomide-dexamethasone followed by lenalidomide for transplant-ineligible multiple myeloma patients: a pooled analysis of two randomized trials.

Bortezomib-melphalan-prednisone (VMP) and continuous lenalidomide-dexamethasone (Rd) represent the standard treatment of transplant-ineligible patients with newly diagnosed multiple myeloma (MM). To date, no randomized trial has compared VMP to Rd, and there is no evidence of the optimal treatment for newly diagnosed MM, particularly in patients with high-risk cytogenetics [del(17p), t(4;14) or t(14;16)]. We pooled together data from patients with newly diagnosed MM treated with VMP or Rd induction followed by lenalidomide maintenance 10 mg (Rd-R) enrolled in the GIMEMA-MM-03-05 and EMN01 trials, to evaluate the efficacy of these treatments in different subgroups of patients, focusing on those with standard- and high-risk cytogenetics. Overall, 474 patients were analyzed (VMP: 257 patients; Rd-R: 217 patients). No differences in progression-free survival (hazard ratio=0.96) and overall survival (hazard ratio=1.08) were observed between standard-risk patients treated with VMP or Rd-R, whereas among the high-risk patients, the probabilities of progression (hazard ratio=0.54) and death (hazard ratio=0.73) were lower in the patients treated with VMP than in those treated with Rd-R. In particular, standard-risk patients >75 years benefited less from VMP than from Rd-R (hazard ratio for progression-free survival=0.96; hazard ratio for overall survival=1.81). In this non-randomized analysis, VMP and Rd-R were equally effective in younger (≤75 years), standard-risk patients, while older ones (>75 years) benefited more from Rd-R. In high-risk patients, VMP improved progression-free survival and overall survival irrespective of age. The source trials are registered at ClinicalTrials.gov (NCT01063179 and NCT01093196).

Development of a screening analytical method for the determination of non-dioxin-like polychlorinated biphenyls in chicken eggs by gaschromatography and electron capture detection.

A sensitive and reproducible screening analytical method is here proposed for the determination of six non dioxin-like polychlorinated biphenyls (NDL-PCBs, congener 28, 52, 101, 138, 153, 180) in chicken eggs based on accelerated solvent extraction (ASE) procedure for the fat extraction and determination, a solid phase extraction (SPE) sample clean-up process, and a gas chromatography - electron capture detection (GC-ECD) analysis. The optimized chromatographic separation, in less than 25 min, returned good responses for the six NDL-PCBs in the range of 2.5-60.0 µg L-1, with correlation coefficients always higher than 0.9995. Instrumental limits of detection were between 0.08-0.35 µg L-1, corresponding to 0.05 and 0.23 ng g-1 fat in the matrix, while method detection limits, calculated on spiked egg samples, ranged from 1.6 to 3.5 ng g-1 fat. The method has been extensively validated in terms of selectivity, sensitivity, recovery, precision, ruggedness and measurement uncertainty, following the European Directives.

Management of women with epilepsy: from preconception to post-partum.

PURPOSE: The physiological changes during pregnancy can significantly alter antiepileptic drug (AED)'s absorption, distribution, metabolism and elimination, thus influencing their plasma concentration. Considering that the risks of using old and new AEDs during pregnancy are still debated, our aim is to review the available evidence on this topic. METHODS: Narrative overview, synthesizing the findings of literature retrieved from searches of computerized databases. RESULTS: The old AEDs generation (benzodiazepines, phenytoin, carbamazepine, phenobarbital and valproic acid) is teratogenic: minor congenital malformations, such as facial dysmorphism and other anomalies, occur in 6-20% of infants exposed to AEDs in utero; this value is two times greater than the value reported in the general population. Major congenital malformations (MCM) such as cleft lip and cleft palate, heart defects (atrial septal defect, Fallot's tetralogy, ventricular septal defect, aortic coarctation, patent ductus arteriosus, and pulmonary stenosis) and urogenital anomalies were estimated to be 4-6% of infants born from mothers treated with AEDs, compared to 2-3% of the general population. CONCLUSION: It is essential to inform women treated with AED that planning pregnancy is necessary, when possible. The problems related to antiepileptic therapy and the possibilities of prenatal diagnosis should be accurately discussed with the patient, when possible before pregnancy: individual circumstances, desire to have children, severity of epilepsy, risks of seizures, family history of congenital malformations and all other potential risk factors must be considered, involving the patient in shared clinical decision-making.

Metacercariae of Galactosomum lacteum (Jägerskiöld, 1896) Looss, 1899 (Heterophyidae) from marine teleosts in the Gulf of Cagliari (southern Sardinia, Italy).

Galactosomum lacteum (Jägerskiöld, 1896) Looss, 1899 metacercariae, encysted on the optic nerve, on the brain and/or on the muscle and the connective of the pharynx and oesophagus, were found in Spicara maena L., S. flexuosa Rafinesque, 1810, S. smaris L. (Centracanthidae), Gobius cruentatus Gmelin, 1789 (Gobiidae), Symphodus tinca L., S. mediterraneus L. (Labridae), Serranus cabrilla L. (Serranidae), Diplodus sargus L. and D. annularis L. (Sparidae) caught in the Gulf of Cagliari (southern Sardinia, Italy). Excysted specimens were identified by some distinctive morphological features: more or less expanded forebody, depending on whether the specimens were living or fixed; tubular excretory bladder extending to the posterior border of the ovary; two-chambered seminal vesicle; asymmetrical and parenchymatous ventral sucker with lines of spines within its cavity; and unarmed gonotyle. Comparison has been made with the congeneric species metacercaria, G. timondavidi Pearson & Prévot, 1971, also registered in the Mediterranean Sea.