Lower Incidence of Dementia Following Cancer Diagnoses: Evidence from a Large Cohort and Mendelian Randomization Study.

BACKGROUND: The reported inverse association between cancer and subsequent Alzheimer's disease and related dementias (ADRD) remains uncertain. OBJECTIVES: To investigate the association between these common conditions of old age and explore possible causal factors. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: We conducted a large population-based cohort analysis using data from 3,021,508 individuals aged 60 and over in the UK Clinical Practice Research Datalink (CPRD), over a period up to 30 years (1988-2018). Cox proportional hazards models were fitted to estimate hazard ratios (HR) for risk of dementia associated with previous cancer diagnosis. Competing risk models were employed to account for competing risk of death. Two-sample Mendelian Randomization analysis based on meta-analysis data from large-scale GWAS studies was also conducted. RESULTS: In the CPRD cohort, 412,903 participants had cancer diagnosis and 230,558 were subsequently diagnosed with dementia over a median follow-up period of 7.9 years. Cancer survivors had a 25% lower risk of developing dementia (HR=0.75, 95% CI:0.74-0.76) after adjustment for potential confounders. Accounting for competing risk of death provided a sub-distribution HR of 0.56 (95% CI:0.55-0.56). Results were consistent for prevalent and incident cancer and different common cancer types. Two-sample Mendelian Randomization analysis, using 357 cancer-related instrumental single-nucleotide polymorphisms (SNPs) revealed evidence of vertical pleiotropy between genetically predicted cancer and reduced risk of Alzheimer's disease (OR=0.97,95% CI:0.95-0.99). CONCLUSION: Our results provide strong epidemiological evidence of the inverse association between cancer and risk of ADRD and support the potential causal nature of this association via genetic instruments. Further investigations into the precise underlying biological mechanisms may reveal valuable information for new therapeutic approaches.

GenoMine: a CRISPR-Cas9-based kill switch for biocontainment of Pseudomonas putida.

Synthetic genetic circuits have revolutionised our capacity to control cell viability by conferring microorganisms with programmable functionalities to limit survival to specific environmental conditions. Here, we present the GenoMine safeguard, a CRISPR-Cas9-based kill switch for the biotechnological workhorse Pseudomonas putida that employs repetitive genomic elements as cleavage targets to unleash a highly genotoxic response. To regulate the system's activation, we tested various circuit-based mechanisms including the digitalised version of an inducible expression system that operates at the transcriptional level and different options of post-transcriptional riboregulators. All of them were applied not only to directly control Cas9 and its lethal effects, but also to modulate the expression of two of its inhibitors: the AcrIIA4 anti-CRISPR protein and the transcriptional repressor TetR. Either upon direct induction of the endonuclease or under non-induced conditions of its inhibitors, the presence of Cas9 suppressed cell survival which could be exploited beyond biocontainment in situations where further CRISPR genome editing is undesirable.

RNA polymerase II transcription initiation in holo-TFIID-depleted mouse embryonic stem cells.

The recognition of core promoter sequences by TFIID is the first step in RNA polymerase II (Pol II) transcription initiation. Metazoan holo-TFIID is a trilobular complex, composed of the TATA binding protein (TBP) and 13 TBP-associated factors (TAFs). Why and how TAFs are necessary for the formation of TFIID domains and how they contribute to transcription initiation remain unclear. Inducible TAF7 or TAF10 depletion, followed by comprehensive analysis of TFIID subcomplex formation, chromatin binding, and nascent transcription in mouse embryonic stem cells, result in the formation of a TAF7-lacking TFIID or a minimal core-TFIID complex, respectively. These partial complexes support TBP recruitment at promoters and nascent Pol II transcription at most genes early after depletion, but importantly, TAF10 is necessary for efficient Pol II pausing. We show that partially assembled TFIID complexes can sustain Pol II transcription initiation but cannot replace holo-TFIID over several cell divisions and/or development.

Seizure forecasting with ultra long-term EEG signals.

OBJECTIVE: The apparent randomness of seizure occurrence affects greatly the quality of life of persons with epilepsy. Since seizures are often phase-locked to multidien cycles of interictal epileptiform activity, a recent forecasting scheme, exploiting RNS data, is capable of forecasting seizures days in advance. METHODS: We tested the use of a bandpass filter to capture the universal mid-term dynamics enabling both patient-specific and cross-patient forecasting. In a retrospective study, we explored the feasibility of the scheme on three long-term recordings obtained by the NeuroPace RNS System, the NeuroVista intracranial, and the UNEEG subcutaneous devices, respectively. RESULTS: Better-than-chance forecasting was observed in 15 (83 %) of 18 patients, and in 16 (89 %) patients for daily and hourly forecast, respectively. Meaningful forecast up to 30 days could be achieved in 4 (22 %) patients for hourly forecast frequency. The cross-patient performance decreased only marginally and was patient-wise strongly correlated with the patient-specific one. Comparable performance was obtained for NeuroVista and UNEEG data sets. SIGNIFICANCE: The feasibility of cross-patient forecasting supports the universal importance of mid-term dynamics for seizure forecasting, demonstrates promising inter-subject-applicability of the scheme on ultra long-term EEG recordings, and highlights its huge potential for clinical use.

Practice and community nurses' views and experiences of helping people manage risk factors for recurrent lower limb cellulitis: A qualitative interview study.

Background: Cellulitis is a painful infection of the skin and underlying tissues, commonly affecting the lower leg. Approximately one-third of people experience recurrence. Nurses who work in general practice (practice nurses) and see people at home (community or district nurses) could have an important role in managing risk factors for cellulitis, such as long-term leg swelling, wound care and skin care. Objective: To explore practice and community nurses' views and experiences of helping people to manage risk factors for recurrent lower limb cellulitis. Methods: Semi-structured, telephone interviews with 21 practice and community nurses in England from October 2020 to March 2021. Interviews were transcribed verbatim and analysed using reflexive thematic analysis. Results: Nurses face multiple challenges when supporting people to manage risk factors for recurrent lower limb cellulitis. Key challenges include limited time and access to resources such as Doppler equipment, and the physical and psychosocial capabilities of patients to self-manage. Nurses identified potential strategies to overcome these challenges, such as placing greater emphasis on prevention and supporting self-management by providing resources for patients and support networks (paid and unpaid carers) to reinforce knowledge post-consultation and develop skills to self-care. Conclusions: We identified a need to develop and evaluate resources, such as support materials, for nurses to use to help patients reduce their risk of recurrent cellulitis.

High-yield production of completely linear dextrans and isomalto-oligosaccharides by a truncated dextransucrase from Ligilactobacillus animalis TMW 1.971.

Several lactic acid bacteria are capable of producing water-soluble exopolysaccharides such as dextran from sucrose by using glucansucrases. Several recombinant glucansucrases were described, however, yields were often limited and most dextrans were branched at position O3. In this study, the dextransucrase from Ligilactobacillus animalis TMW 1.971 was recombinantly produced without its N-terminal variable region and used for dextran synthesis. The enzyme expressed well and showed very high total as well as transferase activities compared to other glucansucrases. It was able to transfer nearly all glucose from sucrose to oligo- and polymeric products under certain conditions (about 95 % of glucose transferred). The high efficiency of the enzyme made it possible to obtain absolute dextran yields of up to 214.9 g/L from a 1.5 M sucrose solution. Structural characterization of the products showed that the dextrans produced have a rather low molecular weight, a narrow size distribution, and are completely linear. Furthermore, we showed that various low molecular weight dextrans or 1,6-linked isomalto-oligosaccharides can be efficiently produced by acid hydrolysis. Overall, we demonstrated that Ligilactobacillus animalis TMW 1.971 dextransucrase can be used to efficiently synthesize dextrans with a quite unique structural composition. The dextrans produced have a high potential for further applications such as synthesis of copolymers or size standards with a very defined molecular structure.

Metabolomic signature identifies HDL and apolipoproteins as potential biomarker for systemic sclerosis with interstitial lung disease.

BACKGROUND: High-density lipoproteins (HDL) affect endothelial functions such as the expression of endothelial cell adhesion molecules and exert anti-apoptotic/-thrombotic functionalities. Therefore, profound analysis of lipoproteins may unveil biomarkers for (micro-)vasculopathy in systemic sclerosis (SSc) and mortality determining disease manifestations like interstitial lung disease (SSc-ILD). Because nuclear magnetic resonance (NMR) spectroscopy provides a wide range of lipoprotein parameters beyond the capabilities of classical analyses it has been used herein to examine lipoprotein profiles in SSc. METHODS: To detect the metabolic and lipidomic profile serum samples from clinically well-characterized SSc patients (n = 100) and age-and sex-matched healthy controls (n = 40) were analyzed by 1H-NMR spectroscopy using Bruker's in-vitro diagnostic research (IVDr) protocol. Statistical analyses were performed to validate significant findings and to search for associations between lipoproteins and clinical phenotypes. RESULTS: Patients with SSc-ILD and lung fibrosis displayed reduced HDL levels. Furthermore, a reduction in apolipoprotein A1 + A2 and its HDL fractions reflected a distinct lipoprotein profile for SSc-ILD patients. This association was independent of potential clinical confounders for dyslipidemia. Notably, in SSc-ILD HDL levels correlate with FVC (forced vital capacity), DLCO (diffusion capacity of the lungs for carbon monoxide), and the modified Rodnan-Skin-Score. CONCLUSION: These results suggest HDL and its lipoproteins may be considered as potential new biomarkers for SSc-ILD. Immune-mediated HDL effects on the endothelium facilitate microvasculopathy - one of the pathophysiological hallmarks in SSc. Therefore, a closer prospective evaluation of the capability of HDL-determination and its lipoproteins regarding a more individualized evaluation of SSc-ILD is warranted.

Development and Evaluation of the OF Pelvis Score for Osteoporotic Pelvic Ring Fractures - A Retrospective Assessment of Therapy Recommendations for 107 Patients. / Entwicklung und Evaluation des OF-Pelvis-Scores bei osteoporotischen Beckenringfrakturen ­ retrospektive Beurteilung der Therapieempfehlung anhand von 107 Patienten.

The aim of this study was to develop a simple and reliable score which supports decision making between non-operative and operative treatment in patients with osteoporotic pelvic fractures.Between 2018 to 2020, the OF Pelvis Score was developed during a total of 5 meetings of the Working Group on Osteoporotic Fractures of the Spine Section of the German Society of Orthopaedics and Trauma. The OF Pelvis Score as a decision aid between non-surgical and surgical treatment was developed by expert consensus after analysis of numerous geriatric sacral and pelvic ring fractures from several hospitals. Subsequently, retrospective evaluation of the score was performed on consecutive patients from three hospitals.The following parameters were considered relevant to decision making between non-surgical and surgical treatment and were incorporated into the score: fracture morphology using the OF Pelvis Classification, pain status, level of mobilisation, fracture-related neurological deficits, health status, and the modifiers already integrated into the OF Pelvis classification. If the score is < 8, non-surgical therapy is recommended; if the score is > 8, surgical therapy is recommended; if the score is 8, there is a relative indication for surgery. The OF Pelvis Score was then evaluated retrospectively in a total of 107 patients, according to records. The OF Pelvis Score was 8 points in 4 patients (3.7%), all of whom received surgical treatment. Of the remaining 103 patients, 93 received score-compliant therapy (90.3%). Among these, 4 of the patients who did not receive score-compliant care refused the recommended surgery, so the actual therapy recommendation was score-compliant in 94.2%.The OF Pelvis Score can be used to derive a therapy recommendation in many patients in clinical practice. Because of the possible change of clinical parameters during the course of the disease, the score has a dynamic character. In the retrospective evaluation, the recommendations from the OF Pelvis Score were in close accordance with the therapy actually performed.

Finding non-fluorinated alternatives to fluorinated gases used as refrigerants.

Hydrofluorocarbons (HFCs) and so-called hydrofluoroolefins (HFOs) are used as refrigerants in air conditioning, refrigeration, chillers, heat pumps and devices for dehumidification and drying. However, many HFCs, including R-134a and R-125, have a high global warming potential and some of the HFCs and HFOs degrade atmospherically and form trifluoroacetic acid (TFA) as a persistent degradation product. Rising levels of TFA around the globe reveal an urgent need to replace fluorinated refrigerants with non-fluorinated working fluids to avoid direct emissions due to leakage, incorrect loading or removal. It is important, however, also to select refrigerants with high efficiencies to avoid increasing indirect CO2 emissions due to higher energy consumption during the use phase. The present study investigates the available non-fluorinated alternatives to fluorinated refrigerants and shows that a transition to non-fluorinated refrigerants, in general, is possible and has happened in many sectors already. Technically, there are only slight barriers to overcome in order to replace fluorinated refrigerants in almost all newly developed systems conforming to existing standards. Additionally, we show that alternatives are available even for some use cases for which derogations have been proposed in the EU PFAS restriction proposal and suggest making these derogations more specific to support a speedy transition to non-fluorinated refrigerants in all sectors.