Very-High Energy γ-ray observations of the Geminga pulsar with the LST-1 of CTA

The improvements in the ground-based techniques for γ-ray detection, particularly the Imaging Atmospheric Cherenkov Telescopes (IACTs), allowed the development of Very-High Energy (VHE) astronomy. Nowadays, more than 250 sources populate the TeV sky, and the number is expected to rise when the Cherenkov Telescope Array Observatory (CTAO) will see its first light. It will consist of two arrays composed of IACTs with three different designs to cover the energy range from 20 GeV to 300 TeV. The telescope design tailored for the lowest energies is the Large-Sized Telescope (LST) and the first one, dubbed LST-1, has been operating since 2019, focusing on extragalactic sources, transients and pulsars. The detection of VHE emission from pulsars was one of the most unexpected discoveries of the last few years. Up to now, only three VHE pulsars are known, and the mechanism responsible for their emission is still unclear. The last discovered one is Geminga, which was detected in 2020 by the MAGIC Collaboration. Geminga was observed also by LST-1 and, for this thesis, 21 hours of good-quality data with a zenith cut at 25° were analysed. The second peak of the light curve was detected at an 8σ significance, and the result of the power law fit of its data was compatible with the one of MAGIC. A joint fit with Fermi-LAT and MAGIC showed the limitations of the present theories, based on curvature radiation, in explaining the VHE emission, and the need for more studies to investigate the presence of additional mechanisms, such as Inverse Compton. Moreover, what has been found proves that the LST-1 has excellent low-energy performance: with one-fourth of MAGIC’s observation time and only one telescope, a stronger signal detection was obtained. This is a crucial result for the science verification of the instrument since it shows that LSTs can consistently improve the performance of current-generation instruments and increase the number of known VHE pulsars

Processi radiativi in Orione

Lo scopo del presente lavoro è mostrare come lo studio dei processi radiativi con spettro continuo sia cruciale, in ambito astrofisico, per ricavare alcuni parametri fisici relativi alle strutture cosmiche. In particolare viene esposto l'esempio della Nebulosa di Orione, per cui è stato possibile ricostruire la morfologia interna grazie all'analisi dello spettro radio continuo e il confronto con gli spettri in riga ottenuti in altre bande di frequenza. Nell'introduzione contenuta nel Capitolo 1 sono esposti la teoria del trasporto radiativo, la radiazione termica di corpo nero e la radiazione da parte di particelle cariche accelerate. Nel Capitolo 2 viene esaminato il processo di bremsstrahlung, o radiazione di frenamento, prodotto dall'interazione tra un elettrone e uno ione liberi. Il Capitolo 3 è dedicato alla radiazione di sincrotrone, caratteristica di particelle cariche ultra-relativistiche immerse in un campo magnetico. Il terzo processo che produce uno spettro continuo, lo scattering Compton inverso, è esaminato nel Capitolo 4. Infine, nel Capitolo 5 è presentato lo studio condotto sulla struttura della Nebulosa di Orione

Twin-to-twin transfusion syndrome: diagnostic imaging and its role in staving off malpractice charges and litigation

The study aims to expound upon the imaging-based diagnostic methodologies aimed at identifying twin-to-twin transfusion syndrome (TTTS), a serious, somewhat rare prenatal condition that takes place in pregnancies where identical twins, or other multiples, share a placenta (monochorionic placenta), highlighting how medico-legal outcomes can be affected by provable compliance with consolidated diagnostic guidelines or best practices. It is of utmost importance to produce a prompt identification of TTTS instances; an early diagnosis is in fact critical in order to effectively treat and manage TTTS. By virtue of TTTS being a highly progressive condition, a delay in diagnosis can result in disastrous outcomes; just a few weeks delay in the diagnosis of TTTS can turn out fatal for one or both twins. Hence, most TTTS malpractice claims involve allegations of medical negligence, namely the failure to recognize the condition in a timely fashion, or to proceed with adequate diagnostic and therapeutic pathways. In that regard, case law databases have been pored over (Justia, Lexis, Leagle), and five significant court cases have been examined and discussed in an attempt to identify objective medico-legal standards and bring to the forefront relevant forensic dynamics. In fact, when health professionals are capable of proving adherence to guidelines or best practices, this can shield them from malpractice allegations and ensuing litigation

Urothelial bladder carcinoma metastasizing to the eye: a systematic review and case report

The eye is a rare site for disseminated malignancies; nevertheless, several tumors may metastasize to ocular structures. Few cases of urothelial and bladder cancer with eye involvement have been described in the literature thus far. The rarity of metastatic ocular localization implies an accurate differential diagnosis among the possible primary tumor sites. However, a specific diagnostic algorithm is not currently available, nor a defined therapeutic approach. Eye metastases are associated with advanced disease and poor prognosis. Physicians should be made aware of the possibility of eye involvement in patients with a past medical history of urothelial bladder cancer associated with ocular symptoms. The present case reports discusses the first documented case, to the best of our knowledge, of an urothelial bladder cancer metastasizing to the retro bulbar region that infiltrates the lacrimal gland. Furthermore, the report provides a systematic qualitative review of the current literature on eye metastases from urothelial bladder cancer using the Preferred Reporting Items for Systematic Reviews and Meta Analyses

Health system assessment for access to care after injury in low- or middle-income countries:A mixed methods study from Northern Malawi

Background: Injuries represent a vast and relatively neglected burden of disease affecting low- and middle-income countries (LMICs). While many health systems underperform in treating injured patients, most assessments have not considered the whole system. We integrated findings from 9 methods using a 3 delays approach (delays in seeking, reaching, or receiving care) to prioritise important trauma care health system barriers in Karonga, Northern Malawi, and exemplify a holistic health system assessment approach applicable in comparable settings.Methods and findings: To provide multiple perspectives on each conceptual delay and include data from community-based and facility-based sources, we used 9 methods to examine the injury care health system. The methods were (1) household survey; (2) verbal autopsy analysis; (3) community focus group discussions (FGDs); (4) community photovoice; (5) facility care-pathway process mapping and elucidation of barriers following injury; (6) facility healthcare worker survey; (7) facility assessment survey; (8) clinical vignettes for care process quality assessment of facility-based healthcare workers; and (9) geographic information system (GIS) analysis. Empirical data collection took place in Karonga, Northern Malawi, between July 2019 and February 2020. We used a convergent parallel study design concurrently conducting all data collection before subsequently integrating results for interpretation. For each delay, a matrix was created to juxtapose method-specific data relevant to each barrier identified as driving delays to injury care. Using a consensus approach, we graded the evidence from each method as to whether an identified barrier was important within the health system.We identified 26 barriers to access timely quality injury care evidenced by at least 3 of the 9 study methods. There were 10 barriers at delay 1, 6 at delay 2, and 10 at delay 3. We found that the barriers “cost,” “transport,” and “physical resources” had the most methods providing strong evidence they were important health system barriers within delays 1 (seeking care), 2 (reaching care), and 3 (receiving care), respectively. Facility process mapping provided evidence for the greatest number of barriers—25 of 26 within the integrated analysis. There were some barriers with notable divergent findings between the community- and facility-based methods, as well as among different community- and facility-based methods, which are discussed. The main limitation of our study is that the framework for grading evidence strength for important health system barriers across the 9 studies was done by author-derived consensus; other researchers might have created a different framework.Conclusions: By integrating 9 different methods, including qualitative, quantitative, community-, patient-, and healthcare worker-derived data sources, we gained a rich insight into the functioning of this health system’s ability to provide injury care. This approach allowed more holistic appraisal of this health system’s issues by establishing convergence of evidence across the diverse methods used that the barriers of cost, transport, and physical resources were the most important health system barriers driving delays to seeking, reaching, and receiving injury care, respectively. This offers direction and confidence, over and above that derived from single methodology studies, for prioritising barriers to address through health service development and policy

Heterozygosity for Neuronal Ceroid Lipofuscinosis predisposes to Bipolar Disorder

Objective: Bipolar Disorder (BD) is an heritable chronic mental disorder causing psychosocial impairment, affecting patients with depressive/manic episodes. The familial transmission of BD does not follow any of the simple Mendelian patterns of inheritance. The aim of this study is to describe a new large family with twelve affected BD members: WES was performed in eight of them, three of which were diagnosed for BD, and one was reported as a "borderline" individual. Material and methods: WES data allowed us to select variants in common between the affected subjects, once including and once excluding a "borderline" subject with moderate anxiety and traits of obsessive-compulsive disorder. Results: Results were in favor of new predisposing BD genes, electing a heterozygous missense variant in CLN6 resulting in a "borderline" phenotype that if combined with a heterozygous missense variant in ZNF92 is responsible for the more severe BD phenotype. Both rare missense changes are predicted to disrupt the protein function. Conclusions: Loss of both alleles in CLN6 causes Neuronal Ceroid Lipofuscinosis, a severe progressive neurological disorder of childhood. Our results indicate that heterozygous CLN6 carriers, previously reported as healthy, may be susceptible to bipolar disorder late in life if associated with additional variants in ZNF92

Validation of 34betaE12 immunoexpression in clear cell papillary renal cell carcinoma as a sensitive biomarker

Clear cell papillary renal cell carcinoma (CCPRCC) is a recently recognised neoplasm with a broad spectrum of morphological characteristics, thus representing a challenging differential diagnosis, especially with the low malignant potential multicystic renal cell neoplasms and clear cell renal cell carcinoma. We selected 14 cases of CCPRCC with a wide spectrum of morphological features diagnosed on morphology and CK7 immunoreactivity and analysed them using a panel of immunohistochemical markers, focusing on 34 beta E12 and related CKs 1,5,10 and 14 and several molecular analyses such as fluorescence in situ hybridisation (FISH), array comparative genomic hybridisation (aCGH), VHL methylation, VHL and TCEB1 sequencing and multiplex ligation-dependent probe amplification (MLPA). Twelve of 13 (92%) CCPRCC tumours were positive for 34 beta E12. One tumour without 3p alteration by FISH revealed VHL mutation and 3p deletion at aCGH; thus, it was re-classified as clear cell RCC. We concluded that: (1) immunohistochemical expression of CK7 is necessary for diagnostic purposes, but may not be sufficient to identify CCPRCC, while 34 beta E12, in part due to the presence of CK14 antigen expression, can be extremely useful for the recognition of this tumour; and (2) further molecular analysis of chromosome 3p should be considered to support of CCPRCC diagnosis, when FISH analysis does not evidence the common loss of chromosome 3p.Peer reviewe

Implication of metabolism in the polarization of tumor-associated-macrophages: the mass spectrometry-based point of view

Tumor-associated macrophages (TAMs) represent one of the main tumor-infiltrating immune cell types and are generally categorized into either of two functionally contrasting subtypes, namely classical activated M1 macrophages and alternatively activated M2 macrophages. TAMs showed different activation states that can be represent by the two extremes of the complex profile of macrophages biology, the M1-like phenotype (pro-inflammatory activity) and the M2-like phenotype (anti-inflammatory activity). Based on the tumor type, and grades, TAMs can acquire different functions and properties; usually, the M1-like phenotype is typical of early tumor stages and is associated to an anti-tumor activity, while M2-like phenotype has a pro-inflammatory activity and is related to a poor patients’ prognosis. The classification of macrophages into M1/M2 groups based on well-defined stimuli does not model the infinitely more complex tissue milieu where macrophages (potentially of different origin) would be exposed to multiple signals in different sequential order. This review aims to summarize the recent mass spectrometry-based (MS-based) metabolomics findings about the modifications of metabolism in TAMs polarization in different tumors. The published data shows that MS-based metabolomics is a promising tool to help better understanding TAMs metabolic phenotypes, although it is still poorly applied for TAMs metabolism. The knowledge of key metabolic alterations in TAMs is an essential step for discovering TAMs polarization novel biomarkers and developing novel therapeutic approaches targeting TAM metabolism to repolarize TAMs towards their anti-tumor phenotype