Protocolized reduction of non-resuscitation fluids versus usual care in septic shock patients (REDUSE): a randomized multicentre feasibility trial.

BACKGROUND/PURPOSE: Non-resuscitation fluids constitute the majority of fluid administered for septic shock patients in the intensive care unit (ICU). This multicentre, randomized, feasibility trial was conducted to test the hypothesis that a restrictive protocol targeting non-resuscitation fluids reduces the overall volume administered compared with usual care. METHODS: Adults with septic shock in six Swedish ICUs were randomized within 12 h of ICU admission to receive either protocolized reduction of non-resuscitation fluids or usual care. The primary outcome was the total volume of fluid administered within three days of inclusion. RESULTS: Median (IQR) total volume of fluid in the first three days, was 6008 ml (interquartile range [IQR] 3960-8123) in the restrictive fluid group (n = 44), and 9765 ml (IQR 6804-12,401) in the control group (n = 48); corresponding to a Hodges-Lehmann median difference of 3560 ml [95% confidence interval 1614-5302]; p < 0.001). Outcome data on all-cause mortality, days alive and free of mechanical ventilation and acute kidney injury or ischemic events in the ICU within 90 days of inclusion were recorded in 98/98 (100%), 95/98 (98%) and 95/98 (98%) of participants respectively. Cognition and health-related quality of life at six months were recorded in 39/52 (75%) and 41/52 (79%) of surviving participants, respectively. Ninety out of 134 patients (67%) of eligible patients were randomized, and 15/98 (15%) of the participants experienced at least one protocol violation. CONCLUSION: Protocolized reduction of non-resuscitation fluids in patients with septic shock resulted in a large decrease in fluid administration compared with usual care. A trial using this design to test if reducing non-resuscitation fluids improves outcomes is feasible. TRIAL REGISTRATION: Clinicaltrials.gov, NCT05249088, 18 February 2022. https://clinicaltrials.gov/ct2/show/NCT05249088.

Tracking nuclear motion in single-molecule magnets using femtosecond X-ray absorption spectroscopy.

The development of new data storage solutions is crucial for emerging digital technologies. Recently, all-optical magnetic switching has been achieved in dielectrics, proving to be faster than traditional methods. Despite this, single-molecule magnets (SMMs), which are an important class of magnetic materials due to their nanometre size, remain underexplored for ultrafast photomagnetic switching. Herein, we report femtosecond time-resolved K-edge X-ray absorption spectroscopy (TR-XAS) on a Mn(III)-based trinuclear SMM. Exploiting the elemental specificity of XAS, we directly track nuclear dynamics around the metal ions and show that the ultrafast dynamics upon excitation of a crystal-field transition are dominated by a magnetically active Jahn-Teller mode. Our results, supported by simulations, reveal minute bond length changes from 0.01 to 0.05 Å demonstrating the sensitivity of the method. These geometrical changes are discussed in terms of magneto-structural relationships and consequently our results illustrate the importance of TR-XAS for the emerging area of ultrafast molecular magnetism.

The complex circumstellar environment of supernova 2023ixf.

The early evolution of a supernova (SN) can reveal information about the environment and the progenitor star. When a star explodes in vacuum, the first photons to escape from its surface appear as a brief, hours-long shock-breakout flare1,2, followed by a cooling phase of emission. However, for stars exploding within a distribution of dense, optically thick circumstellar material (CSM), the first photons escape from the material beyond the stellar edge and the duration of the initial flare can extend to several days, during which the escaping emission indicates photospheric heating3. Early serendipitous observations2,4 that lacked ultraviolet (UV) data were unable to determine whether the early emission is heating or cooling and hence the nature of the early explosion event. Here we report UV spectra of the nearby SN 2023ixf in the galaxy Messier 101 (M101). Using the UV data as well as a comprehensive set of further multiwavelength observations, we temporally resolve the emergence of the explosion shock from a thick medium heated by the SN emission. We derive a reliable bolometric light curve that indicates that the shock breaks out from a dense layer with a radius substantially larger than typical supergiants.

Oncological outcomes of standard versus prolonged time to surgery after neoadjuvant chemoradiotherapy for oesophageal cancer in the multicentre, randomised, controlled NeoRes II trial.

BACKGROUND: The optimal time to surgery (TTS) after neoadjuvant chemoradiotherapy (nCRT) for oesophageal cancer is unknown and has traditionally been 4-6 weeks in clinical practice. Observational studies have suggested better outcomes, especially in terms of histological response, after prolonged delay of up to 3 months after nCRT. The NeoRes II trial is the first randomised trial to compare standard to prolonged TTS after nCRT for oesophageal cancer. PATIENTS AND METHODS: Patients with resectable, locally advanced oesophageal cancer were randomly assigned to standard delay of surgery of 4-6 weeks or prolonged delay of 10-12 weeks after nCRT. The primary endpoint was complete histological response of the primary tumour in patients with adenocarcinoma (AC). Secondary endpoints included histological tumour response, resection margins, overall and progression-free survival in all patients and stratified by histologic type. RESULTS: Between February 2015 and March 2019, 249 patients from 10 participating centres in Sweden, Norway and Germany were randomised: 125 to standard and 124 to prolonged TTS. There was no significant difference in complete histological response between AC patients allocated to standard (21%) compared to prolonged (26%) TTS (P = 0.429). Tumour regression, resection margins and number of resected lymph nodes, total and metastatic, did not differ between the allocated interventions. The first quartile overall survival in patients allocated to standard TTS was 26.5 months compared to 14.2 months after prolonged TTS (P = 0.003) and the overall risk of death during follow-up was 35% higher after prolonged delay (hazard ratio 1.35, 95% confidence interval 0.94-1.95, P = 0.107). CONCLUSION: Prolonged TTS did not improve histological complete response or other pathological endpoints, while there was a strong trend towards worse survival, suggesting caution in routinely delaying surgery for >6 weeks after nCRT.

Dual-Energy X-Ray Absorptiometry Derived Adiposity Measures and Pre-Frailty/Frailty among Norwegian Adults: The Tromsø Study 2007-2015.

OBJECTIVES: Aging is associated with changes in body composition. Excess adiposity among older adults has been linked with metabolic syndromes and aggravated age-associated decline in physical functioning. Few longitudinal studies have explored the association between dual-energy X-ray absorptiometry (DXA)-derived total as well as central adiposity measures and frailty. We examined the association of DXA-derived total and central adiposity with pre-frailty/frailty among Norwegian adults after 8 years of follow-up. DESIGN: Prospective observational study. SETTING: Community-dwelling adults from Tromsø, Norway. MEASUREMENTS: Adiposity was defined by fat mass index (FMI) and visceral adipose tissue (VAT) mass assessed using DXA measures. Frailty status was assessed by low grip strength, slow walking speed, exhaustion, unintentional weight loss and low physical activity level. Pre-frail and frail participants at baseline were excluded. Sex-stratified multivariable logistic regression models were used to investigate the association. RESULTS: Participants comprised 234 women (mean age 68 years) and 146 men (mean age 69 years) attending the population-based Tromsø Study in 2007-2008 (Tromsø6) and 2015-2016 (Tromsø7). At the end of follow-up, 25.6% of the women and 27.4% of the men were pre-frail/frail. Compared with women in the lowest tertiles, those in the highest tertile of baseline FMI (odds ratio [OR] 4.42, 95% confidence interval [CI] 1.88-10.35) and VAT mass (OR 2.47, 95% CI 1.10-5.50), respectively had higher odds for pre-frailty/frailty at follow-up. CONCLUSION: We found a higher likelihood of pre-frailty/frailty in later years among women with general and central adiposity in adulthood, highlighting the importance of preventing excess adiposity for healthy aging.

Equatorial restriction of the photoinduced Jahn-Teller switch in Mn(iii)-cyclam complexes.

Ultrafast transient absorption spectra were recorded for solutions of [MnIII(cyclam)(H2O)(OTf)][OTf]2 (cyclam = 1,4,8,11-tetraazacyclotetradecane and OTf = trifluoromethanesulfonate) in water to explore the possibility to restrict the equatorial expansion following photoexcitation of the dxy ← dz2 electronic transition, often resulting in a switch from axial to equatorial Jahn-Teller distortion in MnIII complexes. Strong oscillations were observed in the excited state absorption signal and were attributed to an excited state wavepacket. The structural rigidity of the cyclam ligand causes a complex reaction coordinate with frequencies of 333, 368, 454 and 517 cm-1, and a significantly shorter compressed-state lifetime compared to other MnIII complexes with less restricted equatorial ligands. Complementary density functional theory quantum chemistry calculations indicate a switch from an axially elongated to a compressed structure in the first excited quintet state Q1, which is accompanied by a modulation of the axial tilt angle. Computed harmonic frequencies for the axial stretching mode (∼379 cm-1) and the equatorial expansions (∼410 and 503 cm-1) of the Q1 state agree well with the observed coherences and indicate that the axial bond length contraction is significantly larger than the equatorial expansion, which implies a successful restriction of the wavepacket motion. The weak oscillation observed around 517 cm-1 is assigned to a see-saw motion of the axial tilt (predicted ∼610 cm-1). The results provide insights into the structural perturbations to the molecular evolution along excited state potential energy surfaces of MnIII octahedral complexes and can be used to guide the synthesis of optically controlled MnIII-based single-molecule magnets.

Photoinduced Jahn-Teller switch in Mn(III) terpyridine complexes.

Ultrafast transient absorption spectra were recorded for [Mn(terpy)X3], where X = Cl, F, and N3, to explore photoinduced switching from axial to equatorial Jahn-Teller (JT) distortion. Strong oscillations were observed in the transients, corresponding to a wavepacket on the excited-state potential energy surface with oscillation frequency around 115 cm-1 for all three complexes. Multireference quantum chemistry calculations indicate that the reaction coordinate is a pincer-like motion of the terpyridine ligand arising from bond length changes in the excited state due to the JT switch. We observed long dephasing times of the wavepacket, with times of 620 fs for [Mn(terpy)Cl3], 450 fs for [Mn(terpy)F3], and 370 fs for [Mn(terpy)(N3)3]. The dephasing time of these coherences decreases with an increasing number of vibrational modes at lower energy than the mode dominating the reaction coordinate, suggesting they act as an effective bath to dissipate the excess energy obtained from photoexcitation.

A femtosecond magnetic circular dichroism spectrometer.

We describe the development of a broadband magneto-optical spectrometer with femtosecond temporal resolution. The absorption spectrometer is based on a white-light supercontinuum (∼320 to 750 nm) using shot-to-shot temporal and spectral referencing at 1 kHz. Static and transient absorption spectra using circularly polarized light are collected in a magnetic field. The difference spectra with respect to the external field direction give the static and transient magneto-optical Faraday rotation (magnetic optical rotary dispersion) and ellipticity (magnetic circular dichroism) spectra. An achromatic quarter-wave plate is used, and the impact of the deviation from ideal retardance on the spectra is discussed. Results from solution-based and thin-film samples are used to demonstrate the performance and wide applicability of the instrument. The sensitivities for the static and time-resolved data were found to be 5 and 0.4 mdeg, respectively. The method presents a simple way to measure magneto-optical spectra using a transient absorption spectrometer and an electromagnet.

Governing health data across changing contexts: A focus group study of citizen's views in England, Iceland, and Sweden.

BACKGROUND: The governance structures associated with health data are evolving in response to advances in digital technologies that enable new ways of capturing, using, and sharing different types of data. Increasingly, health data moves between different contexts such as from healthcare to research, or to commerce and marketing. Crossing these contextual boundaries has the potential to violate societal expectations about the appropriate use of health data and diminish public trust. Understanding citizens' views on the acceptability of and preferences for data use in different contexts is essential for developing information governance policies in these new contexts. METHODS: Focus group design presenting data sharing scenarios in England, Iceland, and Sweden. RESULTS: Seventy-one participants were recruited. Participants supported the need for data to help understand the observable world, improve medical research, the quality of public services, and to benefit society. However, participants consistently identified the lack of information, transparency and control as barriers to trusting organisations to use data in a way that they considered appropriate. There was considerable support for fair and transparent data sharing practices where all parties benefitted. CONCLUSION: Data governance policy should involve all stakeholders' perspectives on an ongoing basis, to inform and implement changes to health data sharing practices that accord with stakeholder views. The Findings showed that (1) data should be used for ethical purposes even when there was commercial interest; (2) data subjects and/or public institutions that provide and share data should also receive benefits from the sharing of data; (3) third parties use of data requires greater transparency and accountability than currently exists, (4) there should be greater information provided to empower data subjects.

Burden of in-hospital care in oesophageal cancer: national population-based study.

BACKGROUND: Oesophageal cancer management requires extensive in-hospital care. This cohort study aimed to quantify in-hospital care for patients with oesophageal cancer in relation to intended treatment, and to analyse factors associated with risk of spending a large proportion of survival time in hospital. METHODS: All patients with oesophageal cancer in three nationwide registers over a 10-year period were included. In-hospital care during the first year after diagnosis was evaluated, and the proportion of survival time spent in hospital, stratified by intended treatment (curative, palliative or best supportive care), was calculated. Associations between relevant factors and a greater proportion of survival time in hospital were analysed by multivariable logistic regression. RESULTS: In-hospital care was provided for a median of 39, 26, and 15 days in the first year after diagnosis of oesophageal cancer in curative, palliative, and best supportive care groups respectively. Patients receiving curatively intended treatment spent a median of 12 per cent of their survival time in hospital during the first year after diagnosis, whereas those receiving palliative or best supportive care spent 19 and 23 per cent respectively. Factors associated with more in-hospital care included older age, female sex, being unmarried, and chronic obstructive pulmonary disease. CONCLUSION: The burden of in-hospital care during the first year after diagnosis of oesophageal cancer was substantial. Important clinical and socioeconomic factors were identified that predisposed to a greater proportion of survival time spent in hospital.

Ultrafast photoinduced dynamics in Prussian blue analogues.

New magnetic materials and methods for controlling them are needed to improve data storage technologies. Recent progress has enabled optical detection and manipulation of spins in molecule-based magnets on the femtosecond timescale, which is promising for both increasing the read/write speed but also the data storage density. Experimental developments in femtosecond X-ray free-electron lasers (XFELs) and magneto-optics, in combination with theory advances, have opened up several new avenues to investigate molecule-based magnets. This review discusses the literature concerning ultrafast photoinduced dynamics in Prussian blue analogues (PBAs), which are molecule-based magnets. In PBAs spin-flips and lattice distortions can happen on the 100 fs timescale, which in some analogues lead to photoinduced changes in the long-range magnetic order. The literature and themes covered in this review are of relevance for ultrafast optical control of new multifunctional materials.

Impact of surgical resection rate on survival in gastric cancer: nationwide study.

BACKGROUND: There are marked geographical variations in the proportion of patients undergoing resection for gastric cancer. This study investigated the impact of resection rate on survival. METHODS: All patients with potentially curable gastric cancer between 2006 and 2017 were identified from the Swedish National Register of Oesophageal and Gastric Cancer. The annual resection rate was calculated for each county per year. Resection rates in all counties for all years were grouped into tertiles and classified as low, intermediate or high. Survival was analysed using the Cox proportional hazards model. RESULTS: A total of 3465 patients were diagnosed with potentially curable gastric cancer, and 1934 (55.8 per cent) were resected. Resection rates in the low (1261 patients), intermediate (1141) and high (1063) tertiles were 0-50.0, 50.1-62.5 and 62.6-100 per cent respectively. The multivariable Cox analysis revealed better survival for patients diagnosed in counties during years with an intermediate versus low resection rate (hazard ratio (HR) 0.81, 95 per cent c.i. 0.74 to 0.90; P < 0.001) and high versus low resection rate (HR 0.80, 0.73 to 0.88; P < 0.001). CONCLUSION: This national register study showed large regional variation in resection rates for gastric cancer. A higher resection rate appeared to be beneficial with regard to overall survival for the entire population.

A RAC-GEF network critical for early intestinal tumourigenesis.

RAC1 activity is critical for intestinal homeostasis, and is required for hyperproliferation driven by loss of the tumour suppressor gene Apc in the murine intestine. To avoid the impact of direct targeting upon homeostasis, we reasoned that indirect targeting of RAC1 via RAC-GEFs might be effective. Transcriptional profiling of Apc deficient intestinal tissue identified Vav3 and Tiam1 as key targets. Deletion of these indicated that while TIAM1 deficiency could suppress Apc-driven hyperproliferation, it had no impact upon tumourigenesis, while VAV3 deficiency had no effect. Intriguingly, deletion of either gene resulted in upregulation of Vav2, with subsequent targeting of all three (Vav2-/- Vav3-/- Tiam1-/-), profoundly suppressing hyperproliferation, tumourigenesis and RAC1 activity, without impacting normal homeostasis. Critically, the observed RAC-GEF dependency was negated by oncogenic KRAS mutation. Together, these data demonstrate that while targeting RAC-GEF molecules may have therapeutic impact at early stages, this benefit may be lost in late stage disease.

Vision therapy as part of neurorehabilitation after acquired brain injury - a clinical study in an outpatient setting.

Introduction: Oculomotor (OM) functions may be affected by acquired brain injury (ABI). The ability to benefit from rehabilitation or to perform daily activities may be affected by OM dysfunctions and associated symptoms. The purpose of this study was to investigate the effects of vision therapy (VT) as part of neurorehabilitation after ABI.Materials and Methods: The study included two groups of outpatients (median 49.5-52.0 years, range 27-67) admitted to neurorehabilitation due to moderate to severe ABI. One group received VT while the other group served as controls to monitor the course of OM dysfunctions without VT.Results: The intervention group showed significant improvements in convergence (Z = 2.26, p = .02), vergence facility (Z = -2.16, p = .03) and vergence reserves (Z = -2.44, p < .01 and t = -4.47, DF = 15, p < .01) along with a significant reduction in vision-related symptoms (Z = 2.97, p < .01).Discussion: We conclude that OM issues were frequent and that targeted VT, as part of neurorehabilitation, can be an efficient treatment resulting in improved functions and reduced symptoms. Further study will be required to understand how improved functions link to performance and satisfaction with everyday activities.

Pre-validation of SENS-IS assay for in vitro skin sensitization of medical devices.

According to ISO 10993-1:2018, the skin sensitization potential of all medical devices must be evaluated, and for this endpoint ISO 10993-10:2010 recommends the use of in vivo assays. The goal of the present study was to determine if the in vitro SENS-IS assay could be a suitable alternative to the current in vivo assays. The SENS-IS assay uses the Episkin Large and SkinEthic RHE reconstructed human epidermis models to evaluate marker genes. In our study, the SENS-IS assay correctly identified 13 sensitizers spiked in a non-polar solvent. In a subsequent analysis six medical device silicone samples previously impregnated with sensitizers were extracted with polar and non-polar solvents. The SENS-IS assay correctly identified five of these extracts, while a sixth extract, which contained the weak sensitizer phenyl benzoate, was classified as negative. However, when this extract was concentrated, or a longer exposure time was used, the assay was able to detect phenyl benzoate. The SENS-IS assay was transferred to a naïve laboratory which correctly identified sensitizers in six blinded silicone samples, including the one containing phenyl benzoate. In light of these results, we conclude that the SENS-IS assay is able to correctly identify the presence of sensitizers in medical devices extracts.