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The mutual influence of F and OH groups in neighboring sites in topaz (Al2SiO4(F,OH)2) was investigated using magic angle spinning nuclear magnetic resonance (MAS NMR) and Raman spectroscopy. The splitting of 19F and 1H NMR signals, as well as the OH Raman band, provides evidence for hydrogen bond formation within the crystal structure. Depending on whether a given OH group has another OH group or fluoride as its neighbor, two different hydrogen bond constellations may form: either OH⋯O⋯HO or F⋯H⋯O. The proton accepting oxygen was determined to be part of the SiO4 tetrahedron using 29Si MAS NMR. Comparison of the MAS NMR data between an OH-bearing and an OH-free topaz sample confirms that the 19F signal at −130 ppm stems from F− ions that take part in H⋯F bonds with a distance of ∼ 2.4 Å, whereas the main signal at −135 ppm belongs to fluoride ions with no immediate OH group neighbors. The Raman OH sub-band at 3644 cm−1 stems from OH groups neighboring other OH groups, whereas the sub-band at 3650 cm−1 stems from OH groups with fluoride neighbors, which are affected by H⋯F bridging. The integrated intensities of these two sub-bands do not conform to the expected ratios based on probabilistic calculations from the total OH concentration. This can be explained by (1) a difference in the polarizability of the OH bond between the different hydrogen bond constellations or (2) partial order or unmixing of F and OH, or a combination of both. This has implications for the quantitative interpretation of Raman data on OH bonds in general and their potential use as a probe for structural (dis-)order. No indication of tetrahedrally coordinated Al was found with 27Al MAS NMR, suggesting that the investigated samples likely have nearly ideal Al/Si ratios, making them potentially useful as high-density electron microprobe reference materials for Al and Si, as well as for F.

Abstract While digital computers rely on software-generated pseudo-random number generators, hardware-based true random number generators (TRNGs), which employ the natural physics of the underlying hardware, provide true stochasticity, and power and area efficiency. Research into TRNGs has extensively relied on the unpredictability in phase transitions, but such phase transitions are difficult to control given their often abrupt and narrow parameter ranges (e.g., occurring in a small temperature window). Here we demonstrate a TRNG based on self-oscillations in LaCoO3 that is electrically biased within its spin crossover regime. The LaCoO3 TRNG passes all standard tests of true stochasticity and uses only half the number of components compared to prior TRNGs. Assisted by phase field modeling, we show how spin crossovers are fundamentally better in producing true stochasticity compared to traditional phase transitions. As a validation, by probabilistically solving the NP-hard max-cut problem in a memristor crossbar array using our TRNG as a source of the required stochasticity, we demonstrate solution quality exceeding that using software-generated randomness.

IntroductionExtracellular ATP (eATP) released from damaged cells activates the P2X7 receptor (P2X7R) ion channel on the surface of surrounding cells, resulting in calcium influx, potassium efflux and inflammasome activation. Inherited changes in the P2X7R gene (P2RX7) influence eATP induced responses. Single nucleotide polymorphisms (SNPs) of P2RX7 influence both function and signaling of the receptor, that in addition to ion flux includes pathogen control and immunity.MethodsSubjects (n = 105) were admitted to the ICU at the University Hospital Ulm, Germany between June 2018 and August 2019. Of these, subjects with a diagnosis of sepsis (n = 75), were also diagnosed with septic shock (n = 24), and/or pneumonia (n = 42). Subjects with pneumonia (n = 43) included those without sepsis (n = 1), sepsis without shock (n = 29) and pneumonia with septic shock (n = 13). Out of the 75 sepsis/septic shock patients, 33 patients were not diagnosed with pneumonia. Controls (n = 30) were recruited to the study from trauma patients and surgical patients without sepsis, septic shock, or pneumonia. SNP frequencies were determined for 16 P2RX7 SNPs known to affect P2X7R function, and association studies were performed between frequencies of these SNPs in sepsis, septic shock, and pneumonia compared to controls.ResultsThe loss-of-function (LOF) SNP rs17525809 (T253C) was found more frequently in patients with septic shock, and non-septic trauma patients when compared to sepsis. The LOF SNP rs2230911 (C1096G) was found to be more frequent in patients with sepsis and septic shock than in non-septic trauma patients. The frequencies of these SNPs were even higher in sepsis and septic patients with pneumonia. The current study also confirmed a previous study by our group that showed a five SNP combination that included the GOF SNPs rs208294 (C489T) and rs2230912 (Q460R) that was designated #21211 was associated with increased odds of survival in severe sepsis.DiscussionThe results found an association between expression of LOF P2RX7 SNPs and presentation to the ICU with sepsis, and septic shock compared to control ICU patients. Furthermore, frequencies of LOF SNPs were found to be higher in sepsis patients with pneumonia compared to those without pneumonia. In addition, a five SNP GOF combination was associated with increased odds of survival in severe sepsis. These results suggest that P2RX7 is required to control infection in pneumonia and that inheritance of LOF variants increases the risk of sepsis when associated with pneumonia. This study confirms that P2RX7 genotyping in pneumonia may identify patients at risk of developing sepsis. The study also identifies P2X7R as a target in sepsis associated with an excessive immune response in subjects with GOF SNP combinations.

Background Nasogastric tube (NGT) feeding against a patient's consent is an intervention that clinicians working in specialist mental health in-patient units may need to implement from time to time. Little research has explored clinician, patient and carer perspectives on good practice. Aims To use qualitative data from people with lived experience (PWLE), parents/carers and clinicians, to identify components of best practice when this intervention is required. Method PWLE and parents/carers were recruited via BEAT UK's eating disorder charity. Clinicians were recruited via a post on The British Eating Disorders Society's research page. Semi-structured interviews were administered, transcribed and thematically analysed. Results Thirty-six interviews took place and overlapping themes were identified. Participants spoke in relation to three themes: first, the significance of individualised care; second, the importance of communication; third, the impact of staff relationships. Sub-themes were identified and explored. Conclusions Good care evolved around positive staff relationships and individualised care planning rather than standard processes. The centrality of trust as an important mediator of outcome was identified, and this should be acknowledged in any service that delivers this intervention.

Primary aldosteronism (PA) is the most common cause of endocrine hypertension and is often underdiagnosed. This condition is associated with increased cardiovascular morbidity and mortality in comparison to age and blood pressure matched individuals with essential hypertension (EH). The diagnostic pathway for PA consists of three phases: screening, confirmatory testing, and subtyping. The lack of specificity in the screening step, which relies on the aldosterone to renin ratio, necessitates confirmatory testing. The Endocrine Society’s clinical practice guideline suggests four confirmatory tests, including the fludrocortisone suppression test (FST), saline suppression test (SST), captopril challenge test (CCT), and oral sodium loading test (SLT). There is no universally accepted choice of confirmatory test, with practices varying among centers. The SST and FST are commonly used, but they can be resource-intensive, carry risks such as volume overload or hypokalemia, and are contraindicated in severe/ uncontrolled HTN as well as in cardiac and renal impairment. In contrast, CCT is a safe and inexpensive alternative that can be performed in an outpatient setting and can be applied when other tests are contraindicated. Despite its simplicity and convenience, the variability in captopril dose, testing posture, and diagnostic threshold limit its widespread use. This narrative review evaluates the diagnostic accuracy of the CCT across different populations, addresses controversies in its usage, and proposes recommendations for its use in the diagnosis of PA. Furthermore, suggestions for future research aimed at promoting the wider utilization of the CCT as a simpler, safer, and more cost-effective diagnostic test are discussed.

Abstract Disrupted circadian rhythms have been linked to an increased risk of hypertension and cardiovascular disease. However, many studies show inconsistent findings and are not sufficiently powered for targeted subgroup analyses. Using the UK Biobank cohort, we evaluate the association between circadian rhythm-disrupting behaviours, blood pressure (SBP, DBP) and inflammatory markers in >350,000 adults with European white British ancestry. The independent U-shaped relationship between sleep length and SBP/DBP is most prominent with a low inflammatory status. Poor sleep quality and permanent night shift work are also positively associated with SBP/DBP. Although fully adjusting for BMI in the linear regression model attenuated effect sizes, these associations remain significant. Two-sample Mendelian Randomisation (MR) analyses support a potential causal effect of long sleep, short sleep, chronotype, daytime napping and sleep duration on SBP/DBP. Thus, in the current study, we present a positive association between circadian rhythm-disrupting behaviours and SBP/DBP regulation in males and females that is largely independent of age.

Abstract INTRODUCTION The Finnish Geriatric Intervention Study (FINGER) led to the global dementia risk reduction initiative: World‐Wide FINGERS (WW‐FINGERS). As part of WW‐FINGERS, the Australian AU‐ARROW study mirrors aspects of FINGER, as well as US‐POINTER. METHOD AU‐ARROW is a randomized, single‐blind, multisite, 2‐year clinical trial (n = 600; aged 55–79). The multimodal lifestyle intervention group will engage in aerobic exercise, resistance training and stretching, dietary advice to encourage MIND diet adherence, BrainHQ cognitive training, and medical monitoring and health education. The Health Education and Coaching group will receive occasional health education sessions. The primary outcome measure is the change in a global composite cognitive score. Extra value will emanate from blood biomarker analysis, positron emission tomography (PET) imaging, brain magnetic resonance imaging (MRI), and retinal biomarker tests. DISCUSSION The finalized AU‐ARROW protocol is expected to allow development of an evidence‐based innovative treatment plan to reduce cognitive decline and dementia risk, and effective transfer of research outcomes into Australian health policy. Highlights Study protocol for a single‐blind, randomized controlled trial, the AU‐ARROW Study. The AU‐ARROW Study is a member of the World‐Wide FINGERS (WW‐FINGERS) initiative. AU‐ARROW's primary outcome measure is change in a global composite cognitive score. Extra significance from amyloid PET imaging, brain MRI, and retinal biomarker tests. Leading to development of an innovative treatment plan to reduce cognitive decline.

Background and purposePrimary aldosteronism (PA) is the most common endocrine cause of secondary hypertension with a prevalence of 14% in patients with newly diagnosed hypertension. Patients with PA experience a higher rate of cardiovascular events including stroke when compared to those with blood pressure matched essential hypertension. This systematic review and meta-analysis summarize current evidence on the prevalence of PA in patients with acute stroke or transient ischemic attack (TIA).MethodsTwo reviewers independently reviewed the literature for observational studies on the prevalence of PA in patients with acute stroke or TIA. MEDLINE and Embase were searched for studies up to December 13, 2023.ResultsThree single center studies conducted in Japan, Singapore and China were found to meet the inclusion criteria. The reported prevalence of PA in two cohort studies of adults with stroke or TIA were 3.1% and 4.0% and a third cross-sectional study in adults under 45 years old revealed a prevalence rate of 12.9%. Following a meta-analysis, the pooled prevalence of PA in adults with stroke or TIA is 5.8% [95% CI 1.6%-12.3%].ConclusionsA considerable proportion of patients with stroke or TIA may have PA as the underlying cause of their hypertension. Given the increased risk of stroke associated with PA, clinicians should consider screening for PA in hypertensive patients with stroke or TIA. Further research is needed to evaluate the effect of timing and interfering medications on test results, which will inform an evidence-based approach to testing for PA following TIA or stroke.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022328644.

Despite improvements in outcomes for children with B- and T-cell acute lymphoblastic leukemia (B-ALL and T-ALL), patients with resistant or relapsed disease fare poorly. Previous studies have demonstrated the essential role of cyclin D3 in T-ALL disease initiation and progression and that targeting of the CDK4/6-cyclin D complex can suppress T-ALL proliferation, leading to efficient cell death in animal models. Studies in leukemia and other malignancies, suggest that schedule is important when combining CDK4/6 inhibitors (CDKi) with cytotoxic agents. Based on these observations, we broadened evaluation of two CDKi, palbociclib (PD-0332991, Pfizer) and ribociclib (LEE011, Novartis) in B- and T-ALL as single agent and in combination with conventional cytotoxic chemotherapy, using different schedules in preclinical models. As monotherapy, CDKi caused cell cycle arrest with a significant decrease in S phase entry and were active in vivo across a broad number of patient-derived xenograft samples. Prolonged monotherapy induces resistance, for which we identified a potential novel mechanism using transcriptome profiling. Importantly, simultaneous but not sequential treatment of CDKi with conventional chemotherapy (dexamethasone, L-asparaginase and vincristine) led to improved efficacy compared to monotherapy in vivo. We provide novel evidence that combining CDKi and conventional chemotherapy can be safe and effective. These results led to the rational design of a clinical trial.