Investigating the association between Lamin B1 and genomic instability in B cells

Lamin B1 is a fundamental component of the nuclear meshwork, which regulates diverse cellular processes, including the stabilisation of the nucleus, chromatin organization, and gene regulation. More recent studies revealed that Lamin B1 is involved in the regulation of DNA damage repair and mutagenesis. In B cells, Lamin B1 epigenetically controls somatic hypermutagenesis in the immunoglobulin variable gene (IgV). Furthermore, decreased Lamin B1 is associated with a genomic instability signature and inferior survival of chronic lymphocytic leukaemia (CLL) patients. Despite the recent findings, the role of Lamin B1 in normal germinal centre (GC) B cells and malignant counterparts remains poorly understood. The principal analysis of the whole exome sequencing data revealed a transient Lamin B1 knockdown in lymphoma cells induces de novo mutational clustering outside of the IgV region. Doxycycline-inducible shRNA mediated Lamin B1 knockdown in vitro lymphoma models demonstrated that the removal of Lamin B1 from the nuclear periphery leads to the spontaneous double-strand breaks (DSBs) and elevated localisation of 53BP1, a mediator of the non-homologous end joining (NHEJ) pathway. Lamin B1 depletion was accompanied by increased cell proliferation and altered transcriptional landscape in BL2 cells. To complement the in vitro findings, a GC B cell-specific Lamin B1 knockout (Lamin B1fl/flCγ1cre/+) mouse model revealed that Lamin B1 depleted GC B cells undergo increased DNA damage without the impairment of humoral immune response. Interestingly, an increase of GC B cells and plasmablasts cells was observed in Lamin B1fl/flCγ1cre/+ mice 21 days after immunisation. The sBLISS (in situ labelling and sequencing) identified DSBs hotspots were enriched around transcriptional start sites of highly expressed genes in Lamin B1 depleted B cells and colocalised with genes mutated in lymphoma. A high proportion of DSB locations in mouse GC B cells contained a DNA sequence motif associated with activation-induced deaminase (AID) mutational signature, suggesting the open chromatin is susceptible to AID-mediated DSBs. Contrary to the findings from the functional studies, high Lamin B1 expression correlates with γH2AX in tissues from diffuse large B cell lymphoma (DLBCL) patients. Clinicopathological analysis of Lamin B1 demonstrated that decreased Lamin B1 expression associates with the advanced diagnostic stages and inferior progression-free survival, particularly in DLBCL patients. this study provides further evidence of Lamin B1’s involvment in the maintenance of genomic stability in B cells and has potential clinical applications in B cell-derived lymphomas

Хроническая боль и функциональные нарушения после артроскопических операций по поводу травмы коленного сустава

Arthroscopic interventions are widely used to treat the consequences of the meniscus and anterior cruciate ligament (ACL) injuries. However, the long-term consequences of these surgeries are not always favorable and not in all cases allow to avoid the development of chronic pain and posttraumatic osteoarthritis.Objective: to evaluate the incidence of persistent postoperative pain and the persistence of functional disorders in patients undergoing arthroscopic interventions on the menisci and ACL.Material and methods. The study group consisted of 147 patients (60 women and 87 men, mean age 38.8±12.5 years) who underwent arthroscopic surgery on the knee joint (KJ) in the traumatology and orthopedic department of V.A. Nasonova Research Institute of Rheumatology in 2018– 2021. The condition of patients was assessed by telephone survey and/or online questionnaire. The pain and fatigue levels were assessed on numerical rating scale (NRS, 0–10), as well as the severity of functional disorders on the Lysholm scale (LS).Results and discussion. Moderate or intense knee pain and increased fatigue (≥4 according to NRS) were noted in 11.3% and 14.7% of respondents, respectively. The state of the KJ according to LS in 35.3% of patients was assessed as excellent (95–100 points), in 29.3% – as good (84–94 points), in 21.3% – as satisfactory (65–83 points) and 14.0% – as unsatisfactory (≤64 points).Conclusion. More than 10% of patients after arthroscopic operations on the knee joint experience moderate or severe pain and fatigue, satisfactory and unsatisfactory functional results are observed in 35.4% of cases.Артроскопические вмешательства широко используются для лечения последствий травм мениска и передней крестообразной связки (ПКС). Однако отдаленные последствия этих операций не всегда благоприятны и не во всех случаях позволяют избежать развития хронической боли и посттравматического остеоартрита.Цель исследования – оценить частоту развития стойкой послеоперационной боли и сохранения функциональных нарушений у пациентов, перенесших артроскопические вмешательства на менисках и ПКС.Материал и методы. Исследуемую группу составили 147 пациентов (60 женщин и 87 мужчин, средний возраст – 38,8±12,5 года), которым была проведена артроскопическая операция на коленном суставе (КС) в травматолого-ортопедическом отделении ФГБНУ «Научно-исследовательский институт ревматологии им. В.А. Насоновой» в 2018–2021 гг. Состояние больных оценивалось путем телефонного опроса и/или онлайн-анкетирования. Учитывались степень боли и утомляемости по числовой рейтинговой шкале (ЧРШ, 0–10), а также выраженность функциональных нарушений по шкале Лисхольма (ШЛ).Результаты и обсуждение. Умеренная или интенсивная боль в КС и повышенная утомляемость (≥4 по ЧРШ) были отмечены у 11,3% и 14,7% респондентов соответственно. Состояние КС по ШЛ у 35,3% больных оценивалось как отличное (95–100 баллов), у 29,3% – как хорошее (84–94 балла), у 21,3% – как удовлетворительное (65–83 балла) и у 14,0% – как неудовлетворительное (≤64 балла).Заключение. Более 10% пациентов после артроскопических операций на КС испытывают умеренную или выраженную боль и утомляемость, удовлетворительные и неудовлетворительные функциональные результаты отмечаются в 35,4% случаев

Epidemiology, practice of ventilation and outcome for patients at increased risk of postoperative pulmonary complications

BACKGROUND Limited information exists about the epidemiology and outcome of surgical patients at increased risk of postoperative pulmonary complications (PPCs), and how intraoperative ventilation was managed in these patients. OBJECTIVES To determine the incidence of surgical patients at increased risk of PPCs, and to compare the intraoperative ventilation management and postoperative outcomes with patients at low risk of PPCs. DESIGN This was a prospective international 1-week observational study using the ‘Assess Respiratory Risk in Surgical Patients in Catalonia risk score’ (ARISCAT score) for PPC for risk stratification. PATIENTS AND SETTING Adult patients requiring intraoperative ventilation during general anaesthesia for surgery in 146 hospitals across 29 countries. MAIN OUTCOME MEASURES The primary outcome was the incidence of patients at increased risk of PPCs based on the ARISCAT score. Secondary outcomes included intraoperative ventilatory management and clinical outcomes. RESULTS A total of 9864 patients fulfilled the inclusion criteria. The incidence of patients at increased risk was 28.4%. The most frequently chosen tidal volume (VT) size was 500 ml, or 7 to 9 ml kg1 predicted body weight, slightly lower in patients at increased risk of PPCs. Levels of positive end-expiratory pressure (PEEP) were slightly higher in patients at increased risk of PPCs, with 14.3% receiving more than 5 cmH2O PEEP compared with 7.6% in patients at low risk of PPCs (P < 0.001). Patients with a predicted preoperative increased risk of PPCs developed PPCs more frequently: 19 versus 7%, relative risk (RR) 3.16 (95% confidence interval 2.76 to 3.61), P < 0.001) and had longer hospital stays. The only ventilatory factor associated with the occurrence of PPCs was the peak pressure. CONCLUSION The incidence of patients with a predicted increased risk of PPCs is high. A large proportion of patients receive high VT and low PEEP levels. PPCs occur frequently in patients at increased risk, with worse clinical outcome

Epidemiology, practice of ventilation and outcome for patients at increased risk of postoperative pulmonary complications: LAS VEGAS - An observational study in 29 countries

BACKGROUND Limited information exists about the epidemiology and outcome of surgical patients at increased risk of postoperative pulmonary complications (PPCs), and how intraoperative ventilation was managed in these patients. OBJECTIVES To determine the incidence of surgical patients at increased risk of PPCs, and to compare the intraoperative ventilation management and postoperative outcomes with patients at low risk of PPCs. DESIGN This was a prospective international 1-week observational study using the ‘Assess Respiratory Risk in Surgical Patients in Catalonia risk score’ (ARISCAT score) for PPC for risk stratification. PATIENTS AND SETTING Adult patients requiring intraoperative ventilation during general anaesthesia for surgery in 146 hospitals across 29 countries. MAIN OUTCOME MEASURES The primary outcome was the incidence of patients at increased risk of PPCs based on the ARISCAT score. Secondary outcomes included intraoperative ventilatory management and clinical outcomes. RESULTS A total of 9864 patients fulfilled the inclusion criteria. The incidence of patients at increased risk was 28.4%. The most frequently chosen tidal volume (V T) size was 500 ml, or 7 to 9 ml kg−1 predicted body weight, slightly lower in patients at increased risk of PPCs. Levels of positive end-expiratory pressure (PEEP) were slightly higher in patients at increased risk of PPCs, with 14.3% receiving more than 5 cmH2O PEEP compared with 7.6% in patients at low risk of PPCs (P ˂ 0.001). Patients with a predicted preoperative increased risk of PPCs developed PPCs more frequently: 19 versus 7%, relative risk (RR) 3.16 (95% confidence interval 2.76 to 3.61), P ˂ 0.001) and had longer hospital stays. The only ventilatory factor associated with the occurrence of PPCs was the peak pressure. CONCLUSION The incidence of patients with a predicted increased risk of PPCs is high. A large proportion of patients receive high V T and low PEEP levels. PPCs occur frequently in patients at increased risk, with worse clinical outcome.</p

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P &lt; 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P &lt; 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Seniorenwohngemeinschaft Tante Mitzi

Titelübersetzung des Autors: Community Living for the Elderly - TANTE MITZIZsfassung in engl. SpracheDemographischer Wandel und geänderte Nutzungsanforderungen der jungen Generation sind hauptverantwortlich für die Zersiedelung der Dörfer im ländlichen Gebiet. Die ehemals um einen zentralen Anger gewachsene Dorfstruktur wird heute durch Einfamilienhaus-Siedlungen am Ortsrand abgelöst. Das Dorf breitet sich in seine Umgebung aus und verdrängt wertvolle Naturund Kulturlandschaft während alte Höfe im Ortskern verfallen und die Dynamik zum Erliegen kommt. Um die Attraktivität der Angerdörfer langfristig zu gewährleisten besteht die Notwendigkeit diese alte Bausubstanz, die charakteristischen ländlichen Hofhäuser, zu reaktivieren. Beim Studienobjekt Tante Mitzi handelt es sich um einen alten Hakenhof in Unterretzbach, im nordwestlichen Weinviertel, der seit über 20 Jahren unbewohnt ist. Das Bauernhaus mit seinen zahlreichen Wirtschaftsräumen und Nebengebäuden entspricht in dieser Form nicht mehr heutigen Wohnbedürfnissen. Ziel ist es daher durch architektonische Interventionen neue Möglichkeiten des Zusammenlebens umzusetzen. Der Hof wird zu einer Seniorenwohngemeinschaft umgebaut. In der dem Projekt zugrundeliegenden Bedarfsanalyse zeigt sich, dass ein derartiges, kollektives Wohnprojekt nicht nur für die OrtsbewohnerInnen (83,5% würden einziehen) sondern auch für WienerInnen (45,5%) attraktiv wäre. Auch seitens des Bürgermeisters und Amtsleiters der Gemeinde Retzbach ist ein standortgerechtes Seniorenwohnprojekt erstrebenswert. Die Baumaßnahmen umfassen vor Allem Renovierung und Adaptierung des bestehenden Hofes sowie eine angepasste Erweiterung. Das Projekt Tante Mitzi soll in Folge als Best Practice Beispiel für weitere Sanierungsprojekte im Ort dienen.Demographic change and transferred usage requirements of the younger generation are some of the main indicators for urban sprawl in the rural area. The original town-structure is under current change because of single-family-housing in the outskirts. The town thereby enlarges into its surrounding area and displaces nature- and culture-landscape while the old farmhouses in the center forfeit. To keep the attraction of the "Angerdörfer" alive it is necessary to reactivate this traditional building substance. The project "Tante Mitzi" is working with an old farmhouse in the town of Unterretzbach in Lower Austria. The house is uninhabitated since over 20 years. The building with several stables and outbuildings is not suitable for modern ways of living anymore. The project aims to create new ways of collective living in the old structures. The farmhouse is being transferred into a collective living residence for seniors. The result of a survey about the project showed that this way of living would be attractive for most of the local inhabitants (83,5%) as well as viennese seniors (45,5%) who would want to move to the countryside. The mayor of Unterretzbach supports the design. The building measures embrace renovation and adoption of the current state of and a suitable add-on. The project Tante Mitzi should work as a best practice example of renovation in town.11

Application of time-frequency spectral analysis methods

In this article the limited application of the non-stationary signals spectra classical analysis using the Fourier transform is substantiated. It is shown that Fourier transform has benefits at periodic signals analysis and limitations when non-stationary signals processing. Authors compared various time-frequency methods of analysis used at signals and circuits in dynamic state. The examples of Fourier window transform application are considered. The dynamic transmission coefficient method for second order circuits time-frequency parameters calculation is studied. The advantages of wavelet transforms application at non-stationary signals analysis are stated