Lung ultrasound is a promising screening tool to rule out interstitial lung disease in patients with rheumatoid arthritis.

BACKGROUND AND OBJECTIVE: It is still controversial how to screen for interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). We aimed to evaluate the performance of lung ultrasound (LUS) as a screening tool for RA-ILD and to compare it with the performance of chest auscultation, chest x-ray and pulmonary function tests (PFTs). METHODS: Cross-sectional study of consecutive RA patients evaluated at a Rheumatology Clinic in Buenos Aires between January and December 2022. High-resolution computed tomography (HRCT) was the gold standard for diagnosing ILD and was performed within 30 days of the LUS, chest x-ray and PFTs. Investigators were blinded to HRCT results and patients' clinical data. LUS was performed by exploring 14 areas and was considered positive when the sum of B lines was ≥5. Performance for the diagnosis of ILD was reported for each diagnostic test. RESULTS: One hundred and six patients were included; 87 (82%) were women. Median age was 60.9 (±9.5) years-old. A total of 32 (30.2%, 95% CI: 21.6%-39.9%) had ILD. The sensitivity and negative predictive value of LUS were 90.6% (95% CI 75.0%-98.0%) and 94.7% (95% CI 85.4%-98.9%), respectively. LUS performance was superior to that of the other evaluated diagnostic tests for screening ILD. CONCLUSIONS: Given that the US is a low-cost point-of-care tool with a high negative predictive value, it is emerging as a valuable tool for ruling out ILD in patients with RA.

Targeting neural correlates of placebo effects.

Harnessing the placebo effects would prompt critical ramifications for research and clinical practice. Noninvasive brain stimulation (NIBS) techniques, such as transcranial magnetic stimulation and multifocal transcranial electric stimulation, could manipulate the placebo response by modulating the activity and excitability of its neural correlates. To identify potential stimulation targets, we conducted a meta-analysis to investigate placebo-associated regions in healthy volunteers, including studies with emotional components and painful stimuli. Using biophysical modeling, we identified NIBS solutions to manipulate placebo effects by targeting either a single key region or multiple connected areas. Moving to a network-oriented approach, we then ran a quantitative network mapping analysis on the functional connectivity profile of clusters emerging from the meta-analysis. As a result, we suggest a multielectrode optimized montage engaging the connectivity patterns of placebo-associated functional brain networks. These NIBS solutions hope to provide a starting point to actively control, modulate or enhance placebo effects in future clinical studies and cognitive enhancement studies.

Late diagnosis of CHD and its associated factors in Kenya: an analytic cross-sectional study.

INTRODUCTION: Burden of CHD in Africa is generally underestimated mainly due to significant under-reporting and early-related fetal and neonatal mortality. OBJECTIVES: Determine the prevalence and factors associated with late diagnosis of CHD seen at three tertiary care hospitals in Kenya. DESIGN: A cross-sectional study on paediatric patients with CHDs, aged 0-18 years, seen over a 5-year period, between January, 2011 and December, 2016. SETTING: Aga Khan University Hospital Nairobi, Mater Hospital, and Kenyatta National Hospital. METHODS: Patients were stratified into those diagnosed late (>1 year of age) and those diagnosed early (<1 year of age). Multiple logistic regression analysis was done to determine factors associated with late diagnosis. RESULTS: The study enrolled 411 patients, with equal gender distribution. Prevalence of late diagnosis (>1 year of age) of CHD was 60.6% (95% CI 55.7-65.3). Median age at diagnosis was 15 (IQR 5-48) months. Presence of a cardiac murmur (OR = 0.87; 95% CI 0.72-0.92, p-value = 0.016) and level of parental education (OR = 4.99; 95% CI 2.25-11.40, p-value <0001) were associated with a decreased odds of late diagnosis. Other factors like cyanosis, an increase in the number of healthcare workers and healthcare facilities per 10,000 population showed some association with decreased odds of late diagnosis of CHD, but these were not statistically significant. CONCLUSION: Late diagnosis of CHD remains alarmingly high in our setting. Initiatives to enhance early detection and screening of CHD should be adopted to reduce related mortality and morbidity.

Long term mortality and morbidity of Italian soldiers after deployment in Iraq as related to biomarkers assessment: Results of the SIGNUM study.

INTRODUCTION: The health profile of military veterans deployed in foreign operative theatres was assessed by several international studies because of potential exposure to depleted uranium and other pollutants. Here we reported results of 15-year epidemiological surveillance assessing long-term health effects in a cohort of Italian soldiers deployed in Iraq in 2004-2005 and participating in a biomonitoring campaign to identify potential genotoxic exposure to environmental xenobiotics before and after deployment (n = 981, SIGNUM cohort). METHODS: We evaluated mortality and hospitalization risks of the SIGNUM cohort retrospectively until 2016 and 2018 respectively. A wide cohort of military personnel never deployed abroad (n = 114,260) and the general Italian population were used as control populations in risk assessment. Causes of death and diagnoses of hospitalization were derived through deterministic record linkage with official national databases of mortality and hospital discharge. Standardized Mortality Ratio (SMR) and Standardized Hospitalization Ratio (SHR) were computed adjusting according to sex, age, area of birth, and calendar year. Differential pre-post deployment in xenobiotics concentrations and early effect biomarkers (oxidative DNA alterations and micronuclei) measured in blood serum were analysed in relation to cancer hospitalization. RESULTS: Mortality risk due to pathologies was more than halved compared to the general population (SMR = 0.41, 95% CI 0.11-1.05) and not significantly different compared to soldiers never deployed abroad (SMR = 0.69, 95% CI 0.19-1.68). Similarly overall hospitalization risk due to pathologies was decreased with respect to the general population (SHR = 0.86, 95% CI 0.80-0.92) and comparable to the control military group (SHR = 0.99, 95% CI: 0.93-1.06). For haematological cancers a decreased hospitalization risk compared to the Italian general population was observed (SHR = 0.38, 95% CI 0-0.92). No statistically significant differences emerged in the patterns of biomarkers in association with cancer hospitalization. CONCLUSION: The study confirms the so called 'healthy warrior' effect for the SIGNUM veterans and showed no correlation between cancer occurrence and biomonitoring markers measured on field.

Enhancement of semantic integration reasoning by tRNS.

The right hemisphere is involved with the integrative processes necessary to achieve global coherence during reasoning and discourse processing. Specifically, the right temporal lobe has been proven to facilitate the processing of distant associate relationships, such as generating novel ideas. Previous studies showed a specific swing of alpha and gamma oscillatory activity over the right parieto-occipital lobe and the right anterior temporal lobe respectively, when people solve semantic problems with a specific strategy, i.e., insight problem-solving. In this study, we investigated the specificity of the right parietal and temporal lobes for semantic integration using transcranial Random Noise Stimulation (tRNS). We administered a set of pure semantics (i.e., Compound Remote Associates [CRA]) and visuo-semantic problems (i.e., Rebus Puzzles) to a sample of 31 healthy volunteers. Behavioral results showed that tRNS stimulation over the right temporal lobe enhances CRA accuracy (+12%), while stimulation on the right parietal lobe causes a decrease of response time on the same task (-2,100 ms). No effects were detected for Rebus Puzzles. Our findings corroborate the involvement of the right temporal and parietal lobes when solving purely semantic problems but not when they involve visuo-semantic material, also providing causal evidence for their postulated different roles in the semantic integration process and promoting tRNS as a candidate tool to boost verbal reasoning in humans.

Corrigendum to "Activation of Melanocortin Receptors MC1 and MC5 Attenuates Retinal Damage in Experimental Diabetic Retinopathy".

[This corrects the article DOI: 10.1155/2016/7368389.].

Immunofluorescence mapping, electron microscopy and genetics in the diagnosis and sub-classification of inherited epidermolysis bullosa: a single-centre retrospective comparative study of 87 cases with long-term follow-up.

BACKGROUND: Epidermolysis bullosa (EB) comprises a heterogeneous group of skin fragility disorders, classified in four major types based on skin cleavage level, i.e. EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), Kindler EB, and in more than 30 subtypes defined by the combination of laboratory and clinical data, including disease course. OBJECTIVES: Our aims were to address whether, in the age of genomics, electron microscopy (TEM) has still a role in diagnosing EB, and whether the genotype per se may be sufficient to sub-classify EB. METHODS: A thoroughly characterized single-centre EB case series was retrospectively evaluated to compare the power of TEM with immunofluorescence mapping (IFM) in establishing the EB type, and the ability of TEM, IFM and genetics to predict selected EB subtypes, i.e. severe dominant EBS (DEBS), severe JEB, severe recessive DEB (RDEB) and DEB self-improving, using genetic and final diagnosis, respectively, as gold standard. RESULTS: The series consisted of 87 patients, including 44 newborns, with a median follow-up of 54 months. Ninety-five mutations were identified in EB-associated genes, including 25 novel variants. Both IFM and TEM were diagnostic in about all cases of JEB (21/21 for both) and DEB (43/44 for IFM, 44/44 for TEM). TEM sensitivity was superior to IFM for EBS (19/20 vs. 16/19). As to EB subtyping, IFM performed better than genetics in identifying severe JEB cases due to laminin-332 defect (14/14 vs. 10/14) and severe RDEB (eight/nine vs. seven/nine). Genetics had no role in self-improving DEB diagnosis; it almost equalled TEM in predicting severe DEBS (eight/nine vs. nine/nine) and enabled to discriminate dominant from recessive non-severe DEB phenotypes and to identify special subtypes, e.g. DEBS with KLHL24 mutations. CONCLUSIONS: Transmission electron microscopy remains relevant to the diagnosis of EBS. IFM and genetics are essential and complementary tools in the vast majority of EB cases.

The complex phenotype of spinocerebellar ataxia type 48 in eight unrelated Italian families.

BACKGROUND AND PURPOSE: Heterozygous mutations in the STUB1 gene have recently been associated with an autosomal dominant form of spinocerebellar ataxia (SCA) associated with cerebellar cognitive-affective syndrome (CCAS), named SCA48. METHODS: Molecular screening was performed in a cohort of 235 unrelated patients with adult-onset, autosomal dominant (17) or sporadic (218) cerebellar ataxia, negative for pathological trinucleotide expansions in the common SCAs, FRDA and FXTAS loci, by using targeted multigene panels or whole-exome sequencing. Bioinformatics analyses, detailed neurological phenotyping and family segregation studies corroborated the pathogenicity of the novel STUB1 mutations. Clinico-diagnostic findings were reviewed to define the phenotypic spectrum. RESULTS: Eight heterozygous STUB1 mutations were identified, six of which were novel in 11 patients from eight index families, giving an estimated overall frequency of 3.4% (8/235) for SCA48 in our study cohort, rising to 23.5% (4/17) when considering only familial cases. All our SCA48 patients had cerebellar ataxia and dysarthria associated with cerebellar atrophy on brain magnetic resonance imaging; of note, many cases were also associated with parkinsonism, chorea and dystonia. CCAS also occurred frequently, whereas definite signs of pyramidal tract dysfunction and peripheral nervous system involvement were absent. One SCA48 patient presented with hypogonadism, associated with other autoimmune endocrine dysfunctions. CONCLUSIONS: Our results support SCA48 as a significant cause of adult-onset SCA. Besides CCAS, our SCA48 patients often showed movement disorders and other clinical manifestations previously described in SCAR16, linked to biallelic variants in the same gene, thus suggesting a continuous clinical spectrum and significant overlap amongst recessive and dominantly inherited mutations in STUB1.

Trabecular titanium tailored implants in complex acetabular revision surgeries: our experience at minimum 3 years follow-up.

Hip revision surgery in cases with previous multiple reconstructive procedures is a challenging procedure. A custom-made product could be useful to obtain good results. Four cases (2 men and 2 women) of acetabular customized Trabecular Titanium (TT) implants made by 3D printed technology were performed. The mean age at surgery was 51.5 years (range 25-72). Patients were reviewed clinically and radiographically at follow-up. Mean Harris Hip Score increased significantly from 13.9 (range 6.9-20.6) preoperatively to 75.8 (range 53.9-94) at last follow-up (mean 43.5, range: 36-59), showing an improvement in terms of both pain relief, function and joint mobility. Radiographically neither signs of instability, migration nor tilting were observed. TT custom-implant made by high performance of the 3D-printing technology, system modularity, and patient-specific surgical tools permitted good clinical results and an effective restoration of the biomechanical joint parameters in these complex revision cases.

Megaprostheses in the treatment of complex fractures of the distal femur.

Total knee replacement (TKR) is a widely used procedure for the treatment of post-traumatic arthritis. This type of solution has also been used recently for the treatment of acute fractures around the knee, particularly in joints that already presented arthritis before the trauma. In case of complex fractures of the distal femur especially in older or very compromised patients, the use of a segmental implant can be an option of treatment in order to obtain a quicker recovery of the patient allowing early mobilization and weight bearing. The purpose of this paper is to present our experience with segmental TKR in the treatment of complex fractures of the distal femur highlighting the main problems associated with these conditions and focusing on the indications, principles of technique, tips, tricks and pitfalls of this procedure.

A clinical, histopathological and laboratory study of 19 consecutive Italian paediatric patients with chilblain-like lesions: lights and shadows on the relationship with COVID-19 infection.

BACKGROUND: Acral chilblain-like lesions are being increasingly reported during COVID-19 pandemic. However, only few patients proved positivity for SARS-CoV-2 infection. The relationship between this skin manifestation and COVID-19 infection has not been clarified yet. OBJECTIVE: To thoroughly characterize a prospective group of patients with chilblain-like lesions and to investigate the possible relationship with SARS-CoV-2 infection. METHODS: Following informed consent, patients underwent (i) clinical evaluation, (ii) RT-PCR and serology testing for SARS-CoV-2, (iii) digital videocapillaroscopy of finger and toe nailfolds, (iv) blood testing to screen for autoimmune diseases and coagulation anomalies, and (v) skin biopsy for histopathology, direct immunofluorescence and, in selected cases, electron microscopy. RESULTS: Nineteen patients, all adolescents (mean age: 14 years), were recruited. 11/19 (58%) of them and/or their cohabitants reported flu-like symptoms one to two months prior to skin manifestation onset. Lesions were localized to toes and also heels and soles. Videocapillaroscopy showed pericapillary oedema, dilated and abnormal capillaries, and microhaemorrhages both in finger and toe in the majority of patients. Major pathological findings included epidermal basal layer vacuolation, papillary dermis oedema and erythrocyte extravasation, perivascular and perieccrine dermal lymphocytic infiltrate, and mucin deposition in the dermis and hypodermis; dermal vessel thrombi were observed in two cases. Blood examinations were normal. Nasopharyngeal swab for SARS-CoV-2 and IgG serology for SARS-CoV-2 nucleocapsid protein were negative. Importantly, IgA serology for S1 domain of SARS-CoV-2 spike protein was positive in 6 patients and borderline in 3. CONCLUSIONS: Chilblain-like lesions during COVID-19 pandemic have specific epidemiologic, clinical, capillaroscopic and histopathological characteristics, which distinguish them from idiopathic perniosis. Though we could not formally prove SARS-CoV-2 infection in our patients, history data and the detection of anti-SARS-COV-2 IgA strongly suggest a relationship between skin lesions and COVID-19. Further investigations on the mechanisms of SARS-CoV-2 infection in children and pathogenesis of chilblain-like lesions are warranted.

The role of neutrophil activation in determining the outcome of pregnancy and modulation by hormones and/or cytokines.

Neutrophils are often exclusively considered as a first-line innate immune defence, able to rapidly kill or trap pathogens and causing in case of over-activation tissue damage. In the female reproductive tract, however, the presence and activity of neutrophils seems to be tightly regulated. Major players in orchestrating this regulation are cyclical steroid sex hormones present during the menstrual cycle and pregnancy. This review describes the role of sex hormones in regulating directly or indirectly the functionality of neutrophils, the role of neutrophils during fertilization and pregnancy and in controlling viral, fungal and bacterial infection. This review also discusses the consequence of overt neutrophil activation in pregnancy pathologies.

Increase of CSF inflammatory profile in a case of highly active multiple sclerosis.

BACKGROUND: Clinical and imaging follow-up coupled with cerebrospinal fluid (CSF) and possibly serum profiling could provide information on disease activity and disability evolution in multiple sclerosis patients. CASE PRESENTATION: We describe the case of a relapsing-remitting MS patient whose history was characterized by failure of several therapeutic approaches and sustained disease activity. By using a highly sensitive immunoassay methodology, we examined protein expression of 70 inflammatory/cytotoxic molecules in two consecutive paired CSF and serum samples, obtained respectively in 2006 and 2013. At disease diagnosis, elevated CSF protein levels of an inflammatory pattern, including CXCL13, CXCL12, IFNγ, TNF, sTNFR1, IL8, sCD163, APRIL, BAFF, pentraxin III and MMP2 were found compared with a group of controls. At the second lumbar puncture, sustained disease activity was accompanied by considerable (more than 2 fold changes) increase expression of most of these inflammatory molecules while no significant changes in serum inflammatory markers were detected in the two consecutive serum samples. CONCLUSIONS: Elevated CSF protein expression of pro-inflammatory mediators, possibly specifically associated to GM demyelination, could remain stable or increase over time in patients with active multiple sclerosis. We underline the role of fluid analysis in understanding the pathophysiology of the disease and providing information on possible markers of disease activity and evolution.

Successful achievement after heterotopic transplantations of long-term stored ovarian tissue in Hodgkin's lymphoma survivor.

In this case report, we describe the outcomes of two heterotopic transplantations of cryopreserved ovarian tissue performed in a patient with HL, after 11 and 15 years of storage. At the age of 30, the patient underwent laparoscopy to collect ovarian tissue for cryopreservation before chemotherapy and radiotherapy. Eleven years later she experienced premature ovarian failure (POF). As the patient was only interested in endocrine function recovery, two heterotopic ovarian tissue transplantations were performed in the abdominal wall above the rectus muscle respectively 11 and 15 years after cryopreservation. Before transplantation, ovarian samples were analyzed to assess neoplastic contamination and tissue quality. The analysis on thawed ovarian tissue did not reveal micrometastasis and it showed well-preserved follicles and stroma. After both ovarian tissue grafting, menopausal symptoms ceased. The patient had periods approximately every 30-days and hormonal levels were within the premenopausal range. The endocrine function lasted 3-years after the first heterotopic transplantation and is still ongoing after second transplantation. Cryopreservation of ovarian tissue should be proposed to HL patients, as the incidence of POF as a long-term complication is not negligible. In these patients heterotopic transplantation is a useful tool to eliminate menopausal symptoms, preventing osteoporosis and reducing cardiovascular risks.

Clinical activity after fingolimod cessation: disease reactivation or rebound?

BACKGROUND AND PURPOSE: There is debate as to whether the apparent rebound after fingolimod discontinuation is related to the discontinuation itself or whether it is due to the natural course of highly active multiple sclerosis (MS). Our aim was to survey the prevalence of severe reactivation and rebound after discontinuation of fingolimod in a cohort of Italian patients with MS. METHODS: Patients with relapsing-remitting MS who were treated with fingolimod for at least 6 months and who stopped treatment for reasons that were unrelated to inefficacy were included in the analysis. RESULTS: A total of 100 patients who had discontinued fingolimod were included in the study. Fourteen patients (14%) had a relapse within 3 months after fingolimod discontinuation, and an additional 12 (12%) had a relapse within 6 months. According to this study's criteria, 10 patients (10%) had a severe reactivation. Amongst these patients, five (5%) had a reactivation that was considered to be a rebound. CONCLUSIONS: The present study showed that more than 26% of patients are at risk of having a relapse within 6 months after fingolimod discontinuation. Nevertheless, the risk of severe reactivations and rebound is lower than has been previously described.

Severe multiple sclerosis reactivation during prolonged lymphopenia after dimethyl fumarate discontinuation.

BACKGROUND: Delayed-release dimethyl fumarate (DMF) treatment can be associated with reduced lymphocyte and leucocyte counts, which might persist after DMF discontinuation. CASE PRESENTATION: We report the case of a patient with severe disease reactivation despite prolonged lymphopenia after DMF discontinuation. We describe the frequency and impact of prolonged lymphopenia after DMF discontinuation at two tertiary MS centres. A 36-year-old female patient with multiple sclerosis was switched to DMF after 14 years of treatment with interferon beta-1a. DMF was suspended after 4 months because of persistent lymphopenia for 3 months. Six months later, the patient had a severe relapse with multiple enhancing brain lesions at MRI although lymphopenia was still persistent. Haematological assessment excluded other causes of lymphopenia, which was evaluated as a probable iatrogenic complication of DMF. The patient was treated with i.v. methylprednisolone 1 gr daily for 3 days with clinical recovery. CONCLUSIONS: Prolonged lymphopenia after DMT discontinuation does not protect against disease reactivation. Starting a new immune therapy should be balanced against the option of a "wait and see." A different immunotherapeutic strategy such as an anti-B therapeutic approach could be considered.

How to obtain better results, choice of implant or surgical technique? A new surgical technique with an extramedullary referenced cutting guide and a blended alignment method.

Measured resection and ligament balancing techniques are the most used in TKA; both require, in the majority of knee arthroplasty systems, a femoral intramedullary canal referencing for the distal femoral cut. Fat embolism, activation of coagulation and bleeding may occur from the reamed canal; this can be avoided with different solutions such as navigation, patient specific instruments or the use of an extramedullary device. The FuZionTM tensor was created as a blended method with the purpose to overcome the downsides of both techniques by fusing them. The aim of our study is to present the technique and the preliminary results of a cohort of patients where this instrument was customized and used as an extramedullary cutting guide for the distal femur, matching the distal femoral cut with the proximal tibial cut in order to obtain a guided, kinematically adjusted, alignment and a reduction of post-op blood loss.

Treatment of Vancouver B1, C periprosthetic hip fractures with periprosthetic polyaxial locking plate system: A 3-year follow-up.

The incidence of periprosthetic fractures after primary knee and hip arthroplasty is around 2.5% and is increasing after revision surgery up to 4%. Management of these fractures is often particularly demanding and expensive. The primary aim of the presented study is to describe our experience in using a precontoured periarticular polyaxial standard plating system in a cohort of patients with homogeneous fracture type (Vancouver B1, C), comparing our experience with other surgical solutions. In stable implants, the primary strategies aim for fracture stabilization, leaving the original prosthesis in place. The results of conventional non-locking implants have been mostly poor with complication rates up to 53%. Therefore, today, monoaxial locking plates are strongly recommended. From May 2013 to December 2014, 30 "non-contact bridging plate" (NCB-PP®) were implanted. All fractures were periprosthetic Vancouver B1 or C fractures. In 24 patients, NCB-PP® plating was performed after periprosthetic femoral fracture as primary treatment, in 6 patients, it was performed as secondary fracture treatment after primary plating failure. All surgeons performed lateral femoral approach with ORIF. Average follow up was 36 months. Bony consolidation was confirmed in all patients, bar one, in an average time of 4 months; none of the patients bar one developed mechanical failure or implant breakage. The GOS at 52 weeks was back to the preoperative level in 18 patients and it did not improve at 24 months. The Harris Hip Score at 52 weeks showed a mean score of 80.14 points. Full weight bearing was allowed at mean time of 100 days. None of the patients developed complications that needed subsequent surgery. The use of NCBPP plates has given excellent results in our clinical practice, allowing early postoperative mobilization and recovery.