Structural connectivity‐based topography of the human globus pallidus: Implications for therapeutic targeting in movement disorders

n/

The Olfactory System Revealed: Non-Invasive Mapping by using Constrained Spherical Deconvolution Tractography in Healthy Humans

Although the olfactory sense has always been considered with less interest than the visual, auditive or somatic senses, it does plays a major role in our ordinary life, with important implication in dangerous situations or in social and emotional behaviors. Traditional Diffusion Tensor signal model and related tractography have been used in the past years to reconstruct the cranial nerves, including the olfactory nerve (ON). However, no supplementary information with regard to the pathways of the olfactory network have been provided. Here, by using the more advanced Constrained Spherical Deconvolution (CSD) diffusion model, we show for the first time in vivo and non-invasively that, in healthy humans, the olfactory system has a widely distributed anatomical network to several cortical regions as well as to many subcortical structures. Although the present study focuses on an healthy sample size, a similar approach could be applied in the near future to gain important insights with regard to the early involvement of olfaction in several neurodegenerative disorders

Selection, affinity maturation, and characterization of a human scFv antibody against CEA protein

BACKGROUND: CEA is a tumor-associated antigen abundantly expressed on several cancer types, including those naturally refractory to chemotherapy. The selection and characterization of human anti-CEA single-chain antibody fragments (scFv) is a first step toward the construction of new anticancer monoclonal antibodies designed for optimal blood clearance and tumor penetration. METHODS: The human MA39 scFv, selected for its ability to recognize a CEA epitope expressed on human colon carcinomas, was first isolated from a large semi-synthetic ETH-2 antibody phage library, panned on human purified CEA protein. Subsequently, by in vitro mutagenesis of a gene encoding for the scFv MA39, a new library was established, and new scFv antibodies with improved affinity towards the CEA cognate epitope were selected and characterized. RESULTS: The scFv MA39 antibody was affinity-maturated by in vitro mutagenesis and the new scFv clone, E8, was isolated, typed for CEA family member recognition and its CEACAM1, 3 and 5 shared epitope characterized for expression in a large panel of human normal and tumor tissues and cells. CONCLUSION: The binding affinity of the scFv E8 is in a range for efficient, in vivo, antigen capture in tumor cells expressing a shared epitope of the CEACAM1, 3 and 5 proteins. This new immunoreagent meets all criteria for a potential anticancer compound: it is human, hence poorly or not at all immunogenic, and it binds selectively and with good affinity to the CEA epitope expressed by metastatic melanoma and colon and lung carcinomas. Furthermore, its small molecular size should provide for efficient tissue penetration, yet give rapid plasma clearance

Painting a global picture of basal ganglia network: from past to present!

Since the 70s it has been thought that basal ganglia integrated sensorimotor, associative and limbic inputs and then projected this information through the thalamus to the motor cortex, supplementary motor area and frontal cortex, thus playing a relevant role in planning movement. Recent literature on basal ganglia networks is going beyond the classical “dogma” of dorsal striatum as the main station for cortical inputs in basal ganglia loops and several neurophysiological studies have suggested a more segregated organization of these neural circuits. In the classical view, various tract-tracing methods combined with immunohistochemistry and in situ hybridization demonstrated that the cortical information flows through the basal ganglia via a dual-network model, based on the “direct” and “indirect” routes. However, in addition to these two major projection systems, a glutamatergic hyper-direct pathway between cerebral cortex and subthalamic nucleus has been demonstrated first in monkeys and then in humans. Furthermore, we have recently shown a i) cortico-pallidal connection; ii) a cerebello-pallidal connection; iii) a cerebello nigral connection [1, 2]. Herein, we extensively examined basal ganglia network of fifteen healthy subjects by using probabilistic constrained spherical deconvolution tractography on magnetic resonance diffusion weighted imaging data and we also performed weighted connectivity analysis for each of the subcortical nuclei. In addition, we demonstrated for the first time tractographic evidences of the existence of a direct cortico-nigral pathway in humans. We found that substantia nigra is connected with cerebral cortex as a whole, with the most representative connections involving prefrontal cortex, precentral and postcentral gyri and superior parietal lobule. These findings would strength the hypothesis that the cortico-basal ganglia network consists of several, parallel, segregated, and functionally distinct, but homologous loop, and may be relevant for the comprehension of the pathophysiology of several basal ganglia disorders

Topo-pathological re-wiring in brain structural connectomes of de novo Parkinson’s Disease patients

Although several studies in the last decades have challenged our understanding of Parkinson’s Disease (PD) pathophysiology, an important gap at a network and system level still remains to be filled in order to understand the fundamental changes in high-order motor and non-motor circuits underlying PD symptoms. The wide spectrum of both motor and non-motor symptoms suggests that Parkinson’s Disease may reflect extended alterations of the global brain network, thus justifying the onset of this heterogeneous symptomatology. Such hypothesis would be suitable with the idea of an “associationist” brain, which goes beyond the classic cortical “localizationist” theory. According to the former, the brain might consist of several, segregated and parallel distributed networks around critical and participating cortical epicenters. To the best of our knowledge, only few studies attempted to improve our understanding on structural MRI networks in PD. With the aim of detecting altered topological rewiring of brain networks in early stage de novo PD patients, we reconstructed tractography-based brain structural connectomes [1] in a pilot population of 10 PD patients and 13 controls. Topological features of structural connectomes were computed and compared between the healthy controls group and the group with PD at different level of cut-off. Significant group differences were showed at certain cut-off in the structural connectivity from the measurement of the Local Community Paradigm-correlation (LCPcorr), Characteristic Path Length, Betweenness Centrality and Edge Betweenness Centrality. Increased value of LCPcorr in the pathological group reflects a topological (and not spatial) network local community re-organization of structural interactions between common neighbors nodes [2]. As a result, the PD group has an increased correlation between the number of common neighbors and the number of their internal-interactions across all the structural local communities in the networks. On the other hand, decreased values in Characteristic Path Length, Betweenness Centrality and Edge Betweenness Centrality suggest also a global topological network re-wiring. Taken together these findings strongly indicate altered topological rewiring in de novo PD brain connectome and could shed new light on the pathophysiology of the disease and in the definition of network-based markers for a more quantitative and precise diagnosis

The hidden geometry of the brain

The human brain connectome is a topologically complex, spatially embedded network. One of the characteristic, basic, nonrandom rules on which brain topology relies on is the tendency of brain networks nodes to cluster into modules with high efficiency and short path length, thus reflecting an intrinsic small-world behavior, functionally segregated (local clustering) and integrated (global efficiency) [1]. Although network topology seems to be somehow connected to network geometry, one of the most challenging issues of the current network science is to infer the hidden geometry from the mere topology of a complex network. Here in, aiming at disclosing the latent geometry of the brain, we apply coalescent embedding – a novel advanced technique able to map a given network in the hyperbolic space inferring the node angular coordinates - on different structural brain networks [2]. Interestingly, we show that we can unsupervisedly reconstruct the intrinsic brain geometry with an incredible level of accuracy and that it strongly resembles the known brain anatomy. As a matter of fact, the first rule of organization of brain networks emerging in the hyperbolic space is their structural segregation into two distinct sections corresponding to the left and right hemispheres, which is a simple concept yet quite neglected in previous studies on brain connectomics. In addition, we demonstrate that the human structural brain networks exhibited a significant different geometry in two age range-specific groups. Finally, we show that the intrinsic geometry of Parkinson’s Disease patients is significantly altered compared to the healthy subjects as revealed by two novel latent geometry markers. The present study may bridge the gap between brain networks topology and geometry and may open a completely new scenario towards the realization of latent geometry network markers for the evaluation of brain disorders

Dupilumab in the treatment of severe uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP): A multicentric observational Phase IV real-life study (DUPIREAL)

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with significant morbidity and reduced health-related quality of life. Findings from clinical trials have demonstrated the effectiveness of dupilumab in CRSwNP, although real-world evidence is still limited. Methods This Phase IV real-life, observational, multicenter study assessed the effectiveness and safety of dupilumab in patients with severe uncontrolled CRSwNP (n = 648) over the first year of treatment. We collected data at baseline and after 1, 3, 6, 9, and 12 months of follow-up. We focused on nasal polyps score (NPS), symptoms, and olfactory function. We stratified outcomes by comorbidities, previous surgery, and adherence to intranasal corticosteroids, and examined the success rates based on current guidelines, as well as potential predictors of response at each timepoint. Results We observed a significant decrease in NPS from a median value of 6 (IQR 5–6) at baseline to 1.0 (IQR 0.0–2.0) at 12 months (p < .001), and a significant decrease in Sino-Nasal Outcomes Test-22 (SNOT-22) from a median score of 58 (IQR 49–70) at baseline to 11 (IQR 6–21; p < .001) at 12 months. Sniffin' Sticks scores showed a significant increase over 12 months (p < .001) compared to baseline. The results were unaffected by concomitant diseases, number of previous surgeries, and adherence to topical steroids, except for minor differences in rapidity of action. An excellent-moderate response was observed in 96.9% of patients at 12 months based on EPOS 2020 criteria. Conclusions Our findings from this large-scale real-life study support the effectiveness of dupilumab as an add-on therapy in patients with severe uncontrolled CRSwNP in reducing polyp size and improving the quality of life, severity of symptoms, nasal congestion, and smell

How future surgery will benefit from SARS-COV-2-related measures: a SPIGC survey conveying the perspective of Italian surgeons

COVID-19 negatively affected surgical activity, but the potential benefits resulting from adopted measures remain unclear. The aim of this study was to evaluate the change in surgical activity and potential benefit from COVID-19 measures in perspective of Italian surgeons on behalf of SPIGC. A nationwide online survey on surgical practice before, during, and after COVID-19 pandemic was conducted in March-April 2022 (NCT:05323851). Effects of COVID-19 hospital-related measures on surgical patients' management and personal professional development across surgical specialties were explored. Data on demographics, pre-operative/peri-operative/post-operative management, and professional development were collected. Outcomes were matched with the corresponding volume. Four hundred and seventy-three respondents were included in final analysis across 14 surgical specialties. Since SARS-CoV-2 pandemic, application of telematic consultations (4.1% vs. 21.6%; p < 0.0001) and diagnostic evaluations (16.4% vs. 42.2%; p < 0.0001) increased. Elective surgical activities significantly reduced and surgeons opted more frequently for conservative management with a possible indication for elective (26.3% vs. 35.7%; p < 0.0001) or urgent (20.4% vs. 38.5%; p < 0.0001) surgery. All new COVID-related measures are perceived to be maintained in the future. Surgeons' personal education online increased from 12.6% (pre-COVID) to 86.6% (post-COVID; p < 0.0001). Online educational activities are considered a beneficial effect from COVID pandemic (56.4%). COVID-19 had a great impact on surgical specialties, with significant reduction of operation volume. However, some forced changes turned out to be benefits. Isolation measures pushed the use of telemedicine and telemetric devices for outpatient practice and favored communication for educational purposes and surgeon-patient/family communication. From the Italian surgeons' perspective, COVID-related measures will continue to influence future surgical clinical practice

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients