Small airways in obstructive lung diseases

Określenie drobne drogi oddechowe (DDO) dotyczy oskrzeli poniżej 7. generacji, o średnicy mniejszej niż 2 mm. W artykule przedstawiono dowody, że ta część drzewa oskrzelowego charakteryzuje się pewnymi odmiennymi cechami zarówno w kontekście budowy, fizjologii, jak i patofizjologii. Szczególnie ważną funkcję odgrywają DDO w chorobach obturacyjnych układu oddechowego. U zdrowych osób opór DDO nie jest większy niż 10% całkowitego oporu dróg oddechowych, natomiast u pacjentów chorych na choroby obturacyjne, poprzez nałożenie się elementu zapalnego i skurczowego ich opór może stanowić nawet 60% oporu całkowitego. Zmiany w DDO w astmie oskrzelowej i przewlekłej obturacyjnej chorobie płuc (POChP) są odpowiedzialne także za powstawanie tak zwanej pułapki powietrznej, szczególnie w POChP. Nie ma obecnie doskonałych metod diagnostyki DDO, w zależności od doświadczeń własnych w różnych ośrodkach przeprowadza się tomografię komputerową wysokiej rozdzielczości, badanie pletyzmograficzne całego ciała (stosunku objętości zalegającej/całkowitej ilości zawartego w płucach powietrza [RV/TLC] lub innych parametrów). Pewne nadzieje wiąże się obecnie z połączeniem oscylometrii impulsacyjnej, testu wypłukiwania azotu w jednym wydechu i pomiaru wydychanego tlenku azotu(eNO). Ze względu na coraz szerszą wiedzę o istotnej roli DDO w patofizjologii chorób obturacyjnych, stworzono superdrobne aerozole, których cząstki zarówno teoretycznie, jak i praktycznie (doświadczenia na impaktorze kaskadowym, skany ozonowe po inhalacjach) mogą wnikać do tej części dróg oddechowych. Autorzy przedstawiają wybrane badania z dwiema grupami leków — agonistami receptora b2-adrenergicznego (BA) i wziewnymi glikokortykosteroidami (wGKS). W przypadku tych pierwszych nie udowodniono, że tak głęboka depozycja w drogach oddechowych przekłada się na poprawę efektu klinicznego. Natomiast w przypadku wGKS, głęboka depozycja ultradrobnego aerozolu powoduje możliwość zmniejszenia dawki leku (nawet ponad dwukrotnej) przy utrzymaniu tego samego efektu terapeutycznego (poprawa indeksu terapeutycznego). Reasumując, DDO wydają się być miejscem podstawowych procesów w rozwoju chorób obturacyjnych i w związku z tym celem potencjalnych terapii.The term small airways (SA) applies to the bronchi below 7th generation with diameter smaller than 2 mm. This paper presents data showing that this part of the respiratory system is distinct in terms of its architecture, physiology and pathophysiology. The most important role SA play in obstructive airway diseases. In healthy subjects SA resistance accounts for 10% of the total airway resistance while in patients with obstructive disease, due to the constriction of the airways together with airway inflammation, SA are responsible even for 60% of the total resistance. Changes in SA in asthma and COPD are responsible for air trapping especially prominent in the latter disease. There are no precise tools to diagnose SA. Depending availability and experience HRCT, body pletysmography (RV/TLS plus other parameters) are frequently used. Some hope for the future is placed in combined use of oscilometry, multiple (or single) breath nitrogen wash-out and eNO concentration measurement. Due to our increasing knowledge on the role of SA in airway obstruction ultra-fine particle aerosols have been developed that penetrate to this compartment of the respiratory system (deposition confirmed in cascade impactors as well as by ozone scans after aerosol inhalation). Authors present selected publications investigating whereas deep drug penetration influences its clinical efficacy. For LABAs deposition in SA doesn’t seem to increase their bronchodilating effect. Using ultrafine CS aerosol allows to maintain clinical effects even with half the dose of the active steroid, however. In summary, SA seem to be crucial in obstructive diseases of the airways and therefore constitute an important target for therapy

Surgical treatment of rectal cancer in Poland — a report from a prospective, multi-centre observational study PSSO_01 conducted under the auspices of the Polish Society of Surgical Oncology

Introduction. Since 2016, as part of the PSSO_01 multi-centre research project conducted under the auspices of the Polish Society of Surgical Oncology, clinical data on rectal cancer treatment have been collected. The objective of the study was to illustrate the state of early results of surgical treatment. Material and methods. The research project is multi-centre in nature. Data shall be collected electronically. The study protocol does not impose or suggest any course of procedure. It only systematizes the way data are collected for scientific purposes. The analysis of early results of surgical treatment was compared with the results of population studies from other European countries (Netherlands, Belgium). Results. By the end of June 2018, 736 patients were registered in the study. In 399 (54.2%) an anterior resection was performed. More than half of patients undergoing subsequent surgical treatment (54.2%) receive neoadjuvant treatment, with the percentage of patients undergoing radiotherapy or radiochemical treatment for lower rectal cancer being about 70%. Most patients (96%) are operated in elective procedure. The percentage of laparoscopic surgeries is low (8.6%). Postoperative complications are observed in 21.1% of patients. Severe complications (grades III–V according to Clavien-Dindo classification) occur in 7.6% of patients undergoing surgery. Postoperative mortality is 1.1%. Discussion. Although the project does not have the character of a registry and does not allow for drawing wider conclusions concerning the compliance with the standards of qualification for neoadjuvant treatment, the important information is that more than half of rectal cancer patients receive preoperative treatment, and the percentage of severe postoperative complications does not exceed 10%. Conclusions. The results of the PSSO_01 project are representative and reflect the actual situation concerning surgical treatment of rectal cancer patients in Poland

The surgical treatment of rectal cancer in Poland. The findings of a multi-center observational study by the Polish Society of Surgical Oncology (PSSO-01)

Introduction. PSSO-01, a Polish prospective multi-center project on rectal cancer, started in 2016 with participation on a voluntary basis. This study evaluates the early outcome of the surgical treatment of rectal cancer in Poland according to hospital volume. Material and methods. The dataset derives from 17 clinical centers registered in the PSSO-01 study. From 2016 to 2020, the data of 1,607 patients were collected. Taking into account the number of patients enrolled in the study, the centers were divided into three categories: high volume, medium volume, and low volume. Nominal variables were compared between different categories of centers using the chi-square test. The STROBE guidelines were used to guarantee the reporting of this observational study. Results. More patients with metastatic disease were operated on in the low volume centers (p = 0.020). Neoadjuvant treatment was used in 35%, 52%, and 66% of patients operated on in low, medium, and high volume centers respectively (p < 0.001). Laparoscopic resection in medium volume centers was performed more often than in other centers (p < 0.001). The total rate of postoperative complications related to high, medium, and low centers was 22%, 26%, 18% (p = 0.044). One year following surgery, a stoma was present in 63% of patients. A defunctioning stoma following anterior resection was reversed in only 55% of patients. Anastomotic leakage was the main reason for a non-reversal diverting stoma. Conclusions. The representation of low volume centers in the PSSO-01 study was understated. However, the outcomes may show the actual situation of surgical treatment of rectal cancer in high and medium volume centers in Poland

Pathogenic <i>NR2F1</i> variants cause a developmental ocular phenotype recapitulated in a mutant mouse model.

Funder: National Institute of Health Research Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of OphthalmologyPathogenic NR2F1 variants cause a rare autosomal dominant neurodevelopmental disorder referred to as the Bosch-Boonstra-Schaaf Optic Atrophy Syndrome. Although visual loss is a prominent feature seen in affected individuals, the molecular and cellular mechanisms contributing to visual impairment are still poorly characterized. We conducted a deep phenotyping study on a cohort of 22 individuals carrying pathogenic NR2F1 variants to document the neurodevelopmental and ophthalmological manifestations, in particular the structural and functional changes within the retina and the optic nerve, which have not been detailed previously. The visual impairment became apparent in early childhood with small and/or tilted hypoplastic optic nerves observed in 10 cases. High-resolution optical coherence tomography imaging confirmed significant loss of retinal ganglion cells with thinning of the ganglion cell layer, consistent with electrophysiological evidence of retinal ganglion cells dysfunction. Interestingly, for those individuals with available longitudinal ophthalmological data, there was no significant deterioration in visual function during the period of follow-up. Diffusion tensor imaging tractography studies showed defective connections and disorganization of the extracortical visual pathways. To further investigate how pathogenic NR2F1 variants impact on retinal and optic nerve development, we took advantage of an Nr2f1 mutant mouse disease model. Abnormal retinogenesis in early stages of development was observed in Nr2f1 mutant mice with decreased retinal ganglion cell density and disruption of retinal ganglion cell axonal guidance from the neural retina into the optic stalk, accounting for the development of optic nerve hypoplasia. The mutant mice showed significantly reduced visual acuity based on electrophysiological parameters with marked conduction delay and decreased amplitude of the recordings in the superficial layers of the visual cortex. The clinical observations in our study cohort, supported by the mouse data, suggest an early neurodevelopmental origin for the retinal and optic nerve head defects caused by NR2F1 pathogenic variants, resulting in congenital vision loss that seems to be non-progressive. We propose NR2F1 as a major gene that orchestrates early retinal and optic nerve head development, playing a key role in the maturation of the visual system

Pathogenic NR2F1 variants cause a developmental ocular phenotype recapitulated in a mutant mouse model.

Pathogenic NR2F1 variants cause a rare autosomal dominant neurodevelopmental disorder referred to as the Bosch-Boonstra-Schaaf Optic Atrophy Syndrome. Although visual loss is a prominent feature seen in affected individuals, the molecular and cellular mechanisms contributing to visual impairment are still poorly characterized. We conducted a deep phenotyping study on a cohort of 22 individuals carrying pathogenic NR2F1 variants to document the neurodevelopmental and ophthalmological manifestations, in particular the structural and functional changes within the retina and the optic nerve, which have not been detailed previously. The visual impairment became apparent in early childhood with small and/or tilted hypoplastic optic nerves observed in 10 cases. High-resolution optical coherence tomography imaging confirmed significant loss of retinal ganglion cells with thinning of the ganglion cell layer, consistent with electrophysiological evidence of retinal ganglion cells dysfunction. Interestingly, for those individuals with available longitudinal ophthalmological data, there was no significant deterioration in visual function during the period of follow-up. Diffusion tensor imaging tractography studies showed defective connections and disorganization of the extracortical visual pathways. To further investigate how pathogenic NR2F1 variants impact on retinal and optic nerve development, we took advantage of an Nr2f1 mutant mouse disease model. Abnormal retinogenesis in early stages of development was observed in Nr2f1 mutant mice with decreased retinal ganglion cell density and disruption of retinal ganglion cell axonal guidance from the neural retina into the optic stalk, accounting for the development of optic nerve hypoplasia. The mutant mice showed significantly reduced visual acuity based on electrophysiological parameters with marked conduction delay and decreased amplitude of the recordings in the superficial layers of the visual cortex. The clinical observations in our study cohort, supported by the mouse data, suggest an early neurodevelopmental origin for the retinal and optic nerve head defects caused by NR2F1 pathogenic variants, resulting in congenital vision loss that seems to be non-progressive. We propose NR2F1 as a major gene that orchestrates early retinal and optic nerve head development, playing a key role in the maturation of the visual system

Leczenie chirurgiczne raka odbytnicy w Polsce — raport z prospektywnego, wieloośrodkowego badania obserwacyjnego PSSO_01 prowadzonego pod auspicjami Polskiego Towarzystwa Chirurgii Onkologicznej

Wstęp. Od 2016 roku w ramach wieloośrodkowego projektu badawczego PSSO_01 prowadzonego pod auspicjami Polskiego Towarzystwa Chirurgii Onkologicznej, gromadzone są dane kliniczne dotyczące leczenia raka odbytnicy. Celem pracy było zobrazowanie stanu dotyczącego wczesnych wyników leczenia chirurgicznego. Materiał i metody. Projekt badawczy ma charakter wieloośrodkowy. Dane gromadzone są elektronicznie. Protokół badania nie narzuca ani nie sugeruje żadnego sposobu postępowania, systematyzuje jedynie sposób zbierania danych w celach naukowych. Analiza dotycząca wczesnych wyników leczenia chirurgicznego została porównana z rezultatami populacyjnych badań z innych krajów europejskich (Holandia, Belgia). Wyniki. Do końca czerwca 2018 roku w badaniu zarejestrowano 736 chorych. U 399 (54,2%) wykonano resekcję przednią. Leczenie neoadiuwantowe otrzymała ponad połowa chorych, poddanych następnie leczeniu operacyjne­mu (54,2%), przy czym odsetek pacjentów poddanych radio- bądź radiochemioterapii z powodu raka dolnej części odbytnicy wyniósł około 70%. Większość chorych (96%) operowana była w trybie planowym. Odsetek operacji wykonanych techniką laparoskopową jest niski (8,6%). Powikłania pooperacyjne zaobserwowano u 21,1% chorych. Ciężkie powikłania (III–V st. wg klasyfikacji Claviena-Dindo) sięgały 7,6% operowanych chorych. Śmiertelność po­operacyjna wyniosła 1,1%. Dyskusja. Chociaż projekt nie ma charakteru rejestru i nie pozwala na wyciągniecie szerszych wniosków dotyczących przestrzegania standardów kwalifikacji do leczenia neoadiuwantowego, istotną informacją jest to, że ponad połowa chorych na raka odbytnicy otrzymuje leczenie przedoperacyjne, a odsetek ciężkich powikłań pooperacyjnych nie przekracza 10%. Wnioski. Wyniki projektu PSSO_01 są reprezentatywne i odzwierciedlają faktyczną sytuację dotyczącą leczenia chirurgicznego chorych na raka odbytnicy w Polsce

BLOOM: A 176B-Parameter Open-Access Multilingual Language Model

Large language models (LLMs) have been shown to be able to perform new tasks based on a few demonstrations or natural language instructions. While these capabilities have led to widespread adoption, most LLMs are developed by resource-rich organizations and are frequently kept from the public. As a step towards democratizing this powerful technology, we present BLOOM, a 176B-parameter open-access language model designed and built thanks to a collaboration of hundreds of researchers. BLOOM is a decoder-only Transformer language model that was trained on the ROOTS corpus, a dataset comprising hundreds of sources in 46 natural and 13 programming languages (59 in total). We find that BLOOM achieves competitive performance on a wide variety of benchmarks, with stronger results after undergoing multitask prompted finetuning. To facilitate future research and applications using LLMs, we publicly release our models and code under the Responsible AI License

Mydriasis as a Side Effect of Dinutuximab Immunotherapy in Pediatric Neuroblastoma: A Case Series

Dinutuximab is a monoclonal antibody against disialoganglioside GD2, a glycosphingolipid strongly expressed on neuroblastoma cells and minimally expressed on normal peripheral nerve cells. While dinutuximab improves survival in high-risk pediatric neuroblastoma, it has also been reported to cause side effects of peripheral neuropathy that typically involve the limbs. We report three cases of children with neuroblastoma who developed mydriasis following treatment with dinutuximab

Prevalence and Risk Factors for Pseudotumor Cerebri Syndrome (PTCS) in Pediatric Kidney Transplant Patients

The etiology of pseudotumor cerebri syndrome (PTCS), especially in young children, remains uncertain. Kidney disease has been suggested as a risk factor for developing PTCS. The aim of this study was to determine the prevalence and risk factors for developing PTCS among pediatric kidney transplant recipients

Role of SIRT1 in autoimmune demyelination and neurodegeneration

Abstract Multiple sclerosis (MS) is a demyelinating disease characterized by chronic inflammation of the central nervous system, in which many factors can act together to influence disease susceptibility and progression. SIRT1 is a member of the histone deacetylase class III family of proteins and is an NAD ? -dependent histone and protein deacetylase. SIRT1 can induce chromatin silencing through the deacetylation of histones and plays an important role as a key regulator of a wide variety of cellular and physiological processes including DNA damage, cell survival, metabolism, aging, and neurodegeneration. It has gained a lot of attention recently because many studies in animal models of demyelinating and neurodegenerative diseases have shown that SIRT1 induction can ameliorate the course of the disease. SIRT1 expression was found to be decreased in the peripheral blood mononuclear cells of MS patients during relapses. SIRT1 represents a possible biomarker of relapses and a potential new target for therapeutic intervention in MS. Modulation of SIRT1 may be a valuable strategy for treating or preventing MS and neurodegenerative central nervous system disorders