Effect of Filtered Blood Return on Outcomes of Pulmonary Aspiration Thrombectomy.

OBJECTIVES: Although filtered blood reinfusion (FBR) can be implemented during aspiration thrombectomy for pulmonary embolism (PE), the effectiveness and risks of this technique remain unknown. The purpose of this study was to assess how utilization of FBR affects procedural outcomes. MATERIALS AND METHODS: A total of 171 patients who underwent aspiration thrombectomy for intermediate-high or high risk PE between December 2018 and September 2022 were included, 84 of whom underwent thrombectomy with FBR and 87 without. Demographic data, vital signs, laboratory values, procedural details, pulmonary arterial pressures, transfusion needs, length of hospital stay, and procedure-related complications were recorded. RESULTS: The groups did not differ at baseline, other than the FBR cohort having a higher percentage of females. There was no significant difference in post-procedural vitals or pulmonary arterial pressure. Mean fluoroscopy time and volume of IV contrast were lower in the FBR cohort. The drop in hemoglobin was lower in the FBR group at both 12 (FBR: -1.065; no FBR: -1.742, P: >0.001) and 24 hrs (FBR: -1.526; no FBR: -2.380, P: >0.001) post procedure; accordingly, fewer patients required transfusions in the FRB cohort (FBR: 8; no FBR: 20, P: 0.016). There was no difference in the number or severity of adverse events or duration of Intensive Care Unit or hospital admission. CONCLUSIONS: FBR use during aspiration pulmonary thrombectomy reduces blood loss and transfusion requirements but has no significant effect on surrogate markers of procedural success or adverse event rates.

Biomechanical factors associated with patellofemoral pain in children and adolescents.

To investigate the biomechanical factors associated with patellofemoral pain in children and adolescents. A cross-sectional, population-based study conducted in Brazil from 2019 to 2023, involving students from public schools. Adjusted prevalence ratios and their respective 95% confidence intervals for the outcome in relation to independent variables were calculated for association analysis, adopting a significance level of 5%. Out of the total of 283 students, 152 were female and 182 were aged between 16 and 18 years old. A positive association was observed between the presence of patellofemoral pain and a poor movement quality in both lower limbs (right side: p = 0.04 and left side: p = 0.04) as well as with dynamic valgus of the left lower limb (p < 0.01). Patellofemoral pain in children and adolescents is associated with poor movement quality in the lower limbs and dynamic valgus of the left lower limb. Actions targeting these biomechanical factors may be crucial for early diagnosis and clinical treatment of this disfunction.

CYB561 supports the neuroendocrine phenotype in castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) is associated with resistance to androgen deprivation therapy, and an increase in the population of neuroendocrine (NE) differentiated cells. It is hypothesized that NE differentiated cells secrete neuropeptides that support androgen-independent tumor growth and induce aggressiveness of adjacent proliferating tumor cells through a paracrine mechanism. The cytochrome b561 (CYB561) gene, which codes for a secretory vesicle transmembrane protein, is constitutively expressed in NE cells and highly expressed in CRPC. CYB561 is involved in the α-amidation-dependent activation of neuropeptides, and contributes to regulating iron metabolism which is often dysregulated in cancer. These findings led us to hypothesize that CYB561 may be a key player in the NE differentiation process that drives the progression and maintenance of the highly aggressive NE phenotype in CRPC. In our study, we found that CYB561 expression is upregulated in metastatic and NE prostate cancer (NEPC) tumors and cell lines compared to normal prostate epithelia, and that its expression is independent of androgen regulation. Knockdown of CYB561 in androgen-deprived LNCaP cells dampened NE differentiation potential and transdifferentiation-induced increase in iron levels. In NEPC PC-3 cells, depletion of CYB561 reduced the secretion of growth-promoting factors, lowered intracellular ferrous iron concentration, and mitigated the highly aggressive nature of these cells in complementary assays for cancer hallmarks. These findings demonstrate the role of CYB561 in facilitating transdifferentiation and maintenance of NE phenotype in CRPC through its involvement in neuropeptide biosynthesis and iron metabolism pathways.

LeGenD: determining N-glycoprofiles using an explainable AI-leveraged model with lectin profiling.

Glycosylation affects many vital functions of organisms. Therefore, its surveillance is critical from basic science to biotechnology, including biopharmaceutical development and clinical diagnostics. However, conventional glycan structure analysis faces challenges with throughput and cost. Lectins offer an alternative approach for analyzing glycans, but they only provide glycan epitopes and not full glycan structure information. To overcome these limitations, we developed LeGenD, a lectin and AI-based approach to predict N-glycan structures and determine their relative abundance in purified proteins based on lectin-binding patterns. We trained the LeGenD model using 309 glycoprofiles from 10 recombinant proteins, produced in 30 glycoengineered CHO cell lines. Our approach accurately reconstructed experimentally-measured N-glycoprofiles of bovine Fetuin B and IgG from human sera. Explanatory AI analysis with SHapley Additive exPlanations (SHAP) helped identify the critical lectins for glycoprofile predictions. Our LeGenD approach thus presents an alternative approach for N-glycan analysis.

Diagnostic delay in bronchiectasis: an Italian perspective.

It takes ∼3.5 years to reach a diagnosis of bronchiectasis from onset of symptoms: the long patient's journey in Italy https://bit.ly/46XMWAz.

Quantification of circulating alpha-1-antitrypsin polymers associated with different SERPINA1 genotypes.

OBJECTIVES: Alpha-1-antitrypsin deficiency is a genetic disorder caused by mutations in the SERPINA1 gene encoding alpha-1-antitrypsin (AAT), the major serine protease inhibitor in plasma. Reduced AAT levels are associated with elevated risk of developing emphysema mainly due to uncontrolled activity of neutrophil elastase in the lungs. The prevalent Z-AAT mutant and many rare pathogenic AAT variants also predispose to liver disease due to their accumulation as polymeric chains in hepatocytes. Part of these polymers are secreted into the bloodstream and could represent biomarkers of intra-hepatic accumulation. Moreover, being inactive, they further lower lung protection against proteases. Aim of our study is to accurately quantify the percentage of circulating polymers (CP) in a cohort of subjects with different SERPINA1 genotypes. METHODS: CP concentration was measured in plasma or Dried Blood Spot (DBS) by a sensitive sandwich ELISA based on capture by the polymer-specific 2C1 monoclonal antibody. RESULTS: CP were significantly elevated in patients with the prevalent PI*SZ and PI*ZZ genotypes, with considerable intra-genotype variability. Notably, higher percentage of polymers was observed in association with elevated C-reactive protein. CP levels were also increased in carriers of the Mmalton variant, and of Mprocida, I, Plowell and Mherleen in heterozygosity with Z-AAT. CONCLUSIONS: These findings highlight the importance of implementing CP quantification in a clinical laboratory. Indeed, the variable amount of CP in patients with the same genotype may correlate with the variable severity of the associated lung and liver diseases. Moreover, CP can reveal the polymerogenic potential of newly discovered ultrarare AAT variants.

Reverse sheathing technique for iliocaval thrombectomy in the setting of IVC filters.

The Inari ClotTriever system (Inari Medical, Irvine, California) is safe and effective for the treatment of DVT. However, because it consists of a 31 cm coring device and collection bag that must be extended for use, application may be precluded by available intravascular "running room", such as in the presence of an IVC filter. Here we present a technique for bypassing IVC filters via retrograde deployment of the ClotTriever within a sheath, as illustrated in three cases. This technique extends the applicability of the ClotTriever to locations in which its length would otherwise preclude use.

LaSap vaccine: Immunotherapy and immunochemotherapy associated with allopurinol in dogs naturally infected with Leishmania infantum.

Canine visceral leishmaniasis is a parasitic zoonosis that has a profound impact on public health in countries where it is endemic. Chemotherapeutic treatments cannot keep dogs stable for long periods, and the risk of generating parasitic resistance must be considered. Forty-four symptomatic and naturally infected dogs with Leishmania infantum were tested with two treatment protocols (i) immunotherapy with LaSap vaccine and (ii) immunochemotherapy with LaSap vaccine plus allopurinol. At 90 days after the end of the treatment, it was verified that, although both protocols had generated significant clinical improvements with a greater production of IFN-γ/IL-10, in relation to the parasite load, mainly in the skin, the dogs treated only with immunotherapy maintained the same profile. These results indicate that LaSap is a good strategy to control dog parasitism.

Comparison among populations with severe and intermediate alpha1-antitrypsin deficiency and chronic obstructive pulmonary disease.

BACKGROUND: Severe alpha1-antitrypsin (AAT) deficiency (AATD) is associated with a high risk of airflow obstruction and emphysema. The risk of lung disease in those with intermediate AAT deficiency is unclear. Our aims were to compare pulmonary function, time of onset of symptoms, and indicators of quality of life among patients with severe AATD (PI*ZZ), patients with intermediate AATD (PI*MZ) from the Italian Registry of AATD with a chronic obstructive pulmonary disease (COPD) cohort of patients without AATD (PI*MM). METHODS: We considered a total of 613 patients: 330 with the PI*ZZ genotype, 183 with the PI*MZ genotype and 100 with the PI*MM genotype. Radiological exams, pulmonary function test, and measurement of quality of life have been performed on all cohorts of patients. RESULTS: The three populations differ significantly in terms of age at COPD/AATD diagnosis (P=0.00001), respiratory function (FEV1, FVC, DLCO P<0.001), quality of life (P=0.0001) and smoking history (P<0.0001). PI*ZZ genotype had 24.9 times a higher likelihood of developing airflow obstruction. The MZ genotype is not associated with a significant early risk of airflow obstruction. CONCLUSIONS: The comparison of populations with PI*ZZ, MZ and MM genotypes allows to delineate the role of alpha1-antitrypsin deficiency on respiratory function and on the impact on quality of life, in relation to other risk factors. These results highlight the crucial role of primary and secondary prevention on smoking habits in PI*MZ subjects and the importance of an early diagnosis.

Shedding light on PRAME expression in dysplastic nevi: a cohort study.

Dysplastic nevi represent one of the least agreed-upon entities in dermatopathology despite the existence of established criteria. This study explores preferentially expressed antigen in melanoma (PRAME) in dysplastic nevi, an uncharted area. We examined 22 common melanocytic nevi (CMN), 20 cutaneous melanomas (CM), 48 low-grade dysplastic nevi (LG-DN), and 40 high-grade dysplastic nevi (HG-DN). PRAME was immunohistochemically assessed using a five-tiered system (0 to 4 +). Among CMN, 59% scored 0, 32% scored 1 + , and 9% scored 2 + . CM had score 2 + and 4 + in 11% and 89% of cases, respectively. Among LG-DN, 38% presented score 0, 31% score 1 + , 17% score 2 + , 8% score 3 + , and 6% score 4 + . Thirty per cent of HG-DN demonstrated a score 0, 30% with score 1 + , 15% score 2 + , 10% score 3 + , and 15% score 4 + . Compared to CMN and CM, LG-DN and HG-DN showed heterogeneous expression profiles of PRAME. PRAME positivity effectively distinguished HG-DN from CM with 85% specificity and 80% sensitivity (p < 0.0001). Predictive values were 87% (negative) and 76% (positive). Furthermore, a trend of increased PRAME expression from LG-DN to HG-DN was observed. However, the applicability of PRAME in the differential diagnosis of dysplastic lesions remains unclear as can yield conflicting results with morphology, which remains the primary diagnostic tool for melanocytic lesions.

Pleural Mesothelioma: Treatable Traits of a Heterogeneous Disease.

Pleural mesothelioma is an aggressive disease with diffuse nature, low median survival, and prolonged latency presenting difficulty in prognosis, diagnosis, and treatment. Here, we review all these aspects to underline the progress being made in its investigation and to emphasize how much work remains to be carried out to improve prognosis and treatment.

Reversal of MYB-dependent suppression of MAFB expression overrides leukaemia phenotype in MLL-rearranged AML.

The transcription factor MYB plays a pivotal role in haematopoietic homoeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). We have previously demonstrated that not all AML subtypes display the same dependency on MYB expression and that such variability is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML remains to be further elucidated. Here, we investigate the role of MYB in human leukaemia by performing siRNA-mediated knock-down in cell line models of AML with different driver lesions. We show that the characteristic reduction in proliferation and the concomitant induction of myeloid differentiation that is observed in MLL-rearranged and t(8;21) leukaemias upon MYB suppression is not seen in AML cells with a complex karyotype. Transcriptome analyses revealed that MYB ablation produces consensual increase of MAFB expression in MYB-dependent cells and, interestingly, the ectopic expression of MAFB could phenocopy the effect of MYB suppression. Accordingly, in silico stratification analyses of molecular data from AML patients revealed a reciprocal relationship between MYB and MAFB expression, highlighting a novel biological interconnection between these two factors in AML and supporting new rationales of MAFB targeting in MLL-rearranged leukaemias.

Long-term outcome after brace treatment of Scheuermann's kyphosis: an observational controlled cohort study.

BACKGROUND: In the literature, there are several papers on Scheuermann's kyphosis. It is a structural deformity of the spine that is characterized by anterior wedging of 5° or more of 3 adjacent thoracic vertebral bodies with kyphosis measuring greater than 45° between T5 and T12. Bracing treatment is able to obtain, during skeletal growth, remodeling of the deformed vertebrae. AIM: The aim of this study was to evaluate the effectiveness of conservative treatment in Scheuermann's kyphosis at a minimum follow-up of 10 years. DESIGN: This is an observational controlled cohort study nested in a prospective clinical on-going database in patients with Scheuermann kyphosis. SETTING: Inpatients and outpatients in Rome. METHODS: From a consecutive series of patients included in a prospective database, we selected 158 patients with thoracic Scheuermann's kyphosis who were treated using an anti-gravity brace: 93 males and 65 females. The mean age at the beginning of the treatment was 14 years. The time bracing prescribed was a max of 20 hours daily and a min of 16 hours daily. Weaning was started when a full recovery of vertebral geometry was seen on a lateral radiograph view or when growing was ended. Radiographical measurements were performed on radiographs from a lateral projection at baseline (t1), at the end of the treatment (t2) and at 10 years of minimum follow-up (t3). To avoid the great variance in the range of curve angles in thoracic kyphosis (TK) that rely on the radiological position, X-rays were performed observing the following position: standing with head straight, arms bent at 45° and hands lightly placed on a support. The anterior wedging angle (Alpha) of the apex vertebra and the degrees of the curve (Cobb methods) were analyzed using statistical analysis. RESULTS: The results from our study showed that in 158 patients with TK curves, the mean Cobb angle was 57.6±6.3 SD at baseline, 43.3±7.8 SD at the end of treatment and 44.49±7.4 SD at ten years of follow-up. The alpha angle was 14.43±2.535 SD at baseline and 8.571±3.589 SD at the end of treatment, and after ten years of follow-up, it was 8.654±3.57 SD. The mean duration of treatment was 28.42±12.07 months, and the mean follow-up was 128.3±11.07 months. The difference between baseline and end of treatment, tested with the one-way ANOVA comparisons test, was significant (P<0.0001) for both Cobb angle and alpha; instead, the difference between the end of treatment and follow-up was not significant (P=0.3277). CONCLUSIONS: The results confirm that conservative treatment in Scheuermann's kyphosis during skeletal growth is effective. Bracing treatment can remodel the deformed vertebrae. CLINICAL REHABILITATION IMPACT: At the 10-year follow-up after bracing, kyphosis curve correction was stable over time.

Use of a funneled sheath for embolic protection during removal of thrombosed Simon Nitinol filters.

Inferior vena cava (IVC) filters should be removed when no longer needed, given their association with complications such as thrombosis of the IVC and lower extremities, fracture, migration, and growth into adjacent structures. While this is generally straightforward in the setting of retrievable filters, permanent filters present more of a challenge. In fact, many operators will not attempt to do so for fear of intraprocedural complications, among them, filter fracture and fragment embolization. Despite this, leaving the filters in situ places patients at risk of the complications described above. Here, the authors illustrate a novel technique for retrieving permanent filters using a funneled sheath to protect against embolization.

Lipopolysaccharide-induced sepsis impairs M2R-GIRK signaling in the mouse sinoatrial node.

Sepsis has emerged as a global health burden associated with multiple organ dysfunction and 20% mortality rate in patients. Numerous clinical studies over the past two decades have correlated the disease severity and mortality in septic patients with impaired heart rate variability (HRV), as a consequence of impaired chronotropic response of sinoatrial node (SAN) pacemaker activity to vagal/parasympathetic stimulation. However, the molecular mechanism(s) downstream to parasympathetic inputs have not been investigated yet in sepsis, particularly in the SAN. Based on electrocardiography, fluorescence Ca2+ imaging, electrophysiology, and protein assays from organ to subcellular level, we report that impaired muscarinic receptor subtype 2-G protein-activated inwardly-rectifying potassium channel (M2R-GIRK) signaling in a lipopolysaccharide-induced proxy septic mouse model plays a critical role in SAN pacemaking and HRV. The parasympathetic responses to a muscarinic agonist, namely IKACh activation in SAN cells, reduction in Ca2+ mobilization of SAN tissues, lowering of heart rate and increase in HRV, were profoundly attenuated upon lipopolysaccharide-induced sepsis. These functional alterations manifested as a direct consequence of reduced expression of key ion-channel components (GIRK1, GIRK4, and M2R) in the mouse SAN tissues and cells, which was further evident in the human right atrial appendages of septic patients and likely not mediated by the common proinflammatory cytokines elevated in sepsis.

Glycosylation shapes the efficacy and safety of diverse protein, gene and cell therapies.

Over recent decades, therapeutic proteins have had widespread success in treating a myriad of diseases. Glycosylation, a near universal feature of this class of drugs, is a critical quality attribute that significantly influences the physical properties, safety profile and biological activity of therapeutic proteins. Optimizing protein glycosylation, therefore, offers an important avenue to developing more efficacious therapies. In this review, we discuss specific examples of how variations in glycan structure and glycoengineering impacts the stability, safety, and clinical efficacy of protein-based drugs that are already in the market as well as those that are still in preclinical development. We also highlight the impact of glycosylation on next generation biologics such as T cell-based cancer therapy and gene therapy.

Challenges of Treating ADHD with Comorbid Substance Use Disorder: Considerations for the Clinician.

Adults with attention deficit/hyperactivity disorder (ADHD) often present psychiatric comorbidities and, in particular, substance use disorder (SUD). ADHD-SUD comorbidity is characterized by greater severity of both disorders, earlier age of onset, higher likelihood of polydrug-abuse and suicidal behaviors, more hospitalizations, and lower treatment adherence. At the present stage, research focused on the pharmacological management of ADHD with comorbid SUD in both adolescents and adults is still lacking. Furthermore, while the short-term effects of stimulants are well studied, less is known about the chronic effects of these drugs on dopamine signaling. Current available evidence is consistent in reporting that high doses of stimulant medications in ADHD-SUD subjects have a mild to moderate efficacy on ADHD symptoms. Some data suggest that pharmacological treatment with stimulants may be beneficial for both ADHD symptoms and comorbid cocaine or amphetamine use. However, in the long run, stimulant medications may have a potential risk for misuse. For the absence of potential misuse, atomoxetine is often recommended for ADHD with comorbid cocaine or amphetamine use disorder. However, its efficacy in reducing addictive behavior is not demonstrated. In subjects with other subtypes of SUD, both atomoxetine and stimulant drugs seem to have scarce impact on addictive behavior, despite the improvement in ADHD symptomatology. In this population, ADHD treatment should be combined with SUD-specific strategies.