Effectiveness of a symptom-clinic intervention delivered by general practitioners with an extended role for people with multiple and persistent physical symptoms in England: the Multiple Symptoms Study 3 pragmatic, multicentre, parallel-group, individually randomised controlled trial.

BACKGROUND: People with multiple and persistent physical symptoms have impaired quality of life and poor experiences of health care. We aimed to evaluate the effectiveness of a community-based symptom-clinic intervention in people with multiple and persistent physical symptoms, hypothesising that this symptoms clinic plus usual care would be superior to usual care only. METHODS: The Multiple Symptoms Study 3 was a pragmatic, multicentre, parallel-group, individually randomised controlled trial conducted in 108 general practices in the UK National Health Service in four regions of England between Dec 6, 2018, and June 30, 2023. Participants were individually randomised (1:1) to the symptom-clinic intervention plus usual care or to usual care only via a computer-generated, pseudo-random list stratified by trial centre. Allocation was done by the trial statistician and concealed with a centralised, web-based randomisation system; masking participants was not possible due to the nature of the intervention. The symptom-clinic intervention was a sequence of up to four medical consultations that aimed to elicit a detailed clinical history, fully hear and validate the participant, offer rational explanations for symptoms, and assist the participant to develop ways of managing their symptoms; it was delivered by general practitioners with an extended role. The primary outcome was Patient Health Questionnaire-15 (PHQ-15) score 52 weeks after randomisation, analysed by intention to treat. The trial is registered on the ISRCTN registry (ISRCTN57050216). FINDINGS: 354 participants were randomly assigned; 178 (50%) were assigned to receive the community-based symptoms clinic plus usual care and 176 (50%) were assigned to receive usual care only. At the primary-outcome point of 52 weeks, PHQ-15 scores were 14·1 (SD 3·7) in the group receiving usual care and 12·2 (4·5) in the group receiving the intervention. The adjusted between-group difference of -1·82 (95% CI -2·67 to -0·97) was statistically significantly in favour of the intervention group (p<0·0001). There were 39 adverse events in the group receiving usual care and 36 adverse events in the group receiving the intervention. There were no statistically significant between-group differences in the proportion of participants who had non-serious adverse events (-0·03, 95% CI -0·11 to 0·05) or serious adverse events (0·02, -0·02 to 0·07). No serious adverse event was deemed to be related to the trial intervention. INTERPRETATION: Our symptom-clinic intervention, which focused on explaining persistent symptoms to participants in order to support self-management, led to sustained improvement in multiple and persistent physical symptoms. FUNDING: UK National Institute for Health and Care Research.

Exploring the barriers to, and importance of, participant diversity in early-phase clinical trials: an interview-based qualitative study of professionals and patient and public representatives.

OBJECTIVES: To explore the importance of, and barriers to achieving, diversity in early-phase clinical trials. DESIGN: Qualitative interviews analysed using thematic analysis. SETTING AND PARTICIPANTS: Five professionals (clinical researchers and methodologists) and three patient and public representatives (those with experience of early-phase clinical trials and/or those from ethnic minority backgrounds) were interviewed between June and August 2022. Participants were identified via their institutional web page, existing contacts or social media (eg, X, formerly known as Twitter). RESULTS: Professionals viewed that diversity is not currently considered in all early-phase clinical trials but felt that it should always be taken into account. Such trials are primarily undertaken at a small number of centres, thus limiting the populations they can access. Referrals from clinicians based in the community may increase diversity; however, those referred are often not from underserved groups. Referrals may be hindered by the extra resources required to approach and recruit underserved groups and participants often having to undertake 'self-driven' referrals. Patient and public representatives stated that diversity is important in research staff and that potential participants should be informed of the need for diversity. Those from underserved groups may require clarification regarding the potential harms of a treatment, even if these are unknown. Education may improve awareness and perception of early-phase clinical trials. We provide 14 recommendations to improve diversity in early-phase clinical trials. CONCLUSIONS: Diversity should be considered in all early-phase trials. Consideration is required regarding the extent of diversity and how it is addressed. The increased resources needed to recruit those from underserved groups may warrant funders to increase the funds to support the recruitment of such participants. The potential harms and societal benefits of the research should be presented to potential participants in a balanced but accurate way to increase transparency.

Investigating radical pair reaction dynamics of B12 coenzymes 1: Transient absorption spectroscopy and magnetic field effects.

B12 coenzymes are vital to healthy biological function across nature. They undergo radical chemistry in a variety of contexts, where spin-correlated radical pairs can be generated both thermally and photochemically. Owing to the unusual magnetic properties of B12 radical pairs, however, most of the reaction and spin dynamics occur on a timescale (picoseconds-nanoseconds) that cannot be resolved by most measurement techniques. Here, we describe a method that combines femtosecond transient absorption spectroscopy with magnetic field exposure, which enables the direct scrutiny of such rapid processes. This approach should provide a means by which to investigate the apparently profound effect protein environments have on the generation and reactivity of B12 radical pairs.

Investigating radical pair reaction dynamics of B12 coenzymes 2: Time-resolved electron paramagnetic resonance spectroscopy.

The chemistry of B12 coenzymes is highly sensitive to the nature of their upper axial ligand and can be further tuned by their environment. Methylcobalamin, for example, generates RPs photochemically but undergoes non-radical biochemistry when bound to its dependent enzymes. Owing to the transient nature of the reaction intermediates, it remains a challenge to investigate how their environment controls reactivity. Here, we describe how to use time-resolved electron paramagnetic spectroscopy to directly monitor the generation and evolution of transient radicals that result from the photolysis of a B12 coenzyme. This method produces evolving, spin-polarized spectra that are rich in mechanistic detail.

Socioeconomic Deprivation and Dropout from Contemporary Psychological Intervention for Common Mental Disorders: A Systematic Review.

Dropout during psychological intervention is a significant problem. Previous evidence for associations with socioeconomic deprivation is mixed. This study aimed to review the evidence for associations between deprivation and dropout from contemporary adult psychological interventions for common mental disorders (CMDs). Systematic review, narrative synthesis and random effects meta-analysis of peer-reviewed English language journal articles published June 2010-June 2020 was conducted. Data sources included medline, PsycInfo, databases indexed by web of science, ProQuest social science database and sociology collection, and the Cochrane Library, supplemented by forward and backward citation searching. Five studies were eligible for inclusion (mean N = 170, 68% female, 60% White Caucasian, 32% dropout rate, predominantly cognitive behaviour therapy/cognitive processing therapy). Narrative synthesis indicated an overall non-significant effect of deprivation on dropout. Meta-analytic significance of controlled (k = 3) and uncontrolled (k = 4) effects depended on the measure of deprivation included for those studies using more than one measure (controlled OR 1.21-1.32, p = 0.019-0.172, uncontrolled OR 1.28-1.76, p = 0.024-0.423). The low number of included studies meant sub-group comparisons were limited, despite some tentative indications of potential differential effects. A comparator set of excluded studies showed similar uncertainty. There was limited evidence that did not overall suggest a clear significant effect of deprivation on dropout from contemporary individual CMD interventions. However, more contemporary research is needed, as effects may vary according to clinical and methodological factors, and for dropout versus non-initiation.

Cellular autofluorescence is magnetic field sensitive.

We demonstrate, by direct, single-cell imaging kinetic measurements, that endogenous autofluorescence in HeLa cells is sensitive to the application of external magnetic fields of 25 mT and less. We provide spectroscopic and mechanistic evidence that our findings can be explained in terms of magnetic field effects on photoinduced electron transfer reactions to flavins, through the radical pair mechanism. The observed magnetic field dependence is consistent with a triplet-born radical pair and a B1/2 value of 18.0 mT with a saturation value of 3.7%.

Layer-by-Layer Thinning of PdSe2 Flakes via Plasma Induced Oxidation and Sublimation.

Controlled O2/Ar plasma exposure and subsequent low temperature inert atmosphere annealing of chemical vapor deposition (CVD) grown PdSe2 flakes etch PdSe2 layer-by-layer in an atomic layer etching-like (ALE) process. X-ray photoelectron spectroscopy (XPS) shows that exposure to a remote inductively coupled plasma (ICP) oxygen plasma oxidizes the top layer of the PdSe2 to form PdO2 and SeO2. After an in situ annealing, XPS shows no trace of PdO2 or SeO2, suggesting the byproducts are volatile at low temperature. Atomic force microscopy of PdSe2 exposed to various O2 + Ar plasmas (O2 = 25-100%) demonstrates a clear trend between the oxygen concentration and the number of layers etched per cycle. PdSe2 field effect transistors (FETs) were characterized at various stages of two ALE-like cycles, and the electrical properties are correlated to the oxidation and byproduct desorption and layer reduction.

Observation of the Δg mechanism resulting from the ultrafast spin dynamics that follow the photolysis of coenzyme B12.

Throughout nature, both free radicals and transient radical reaction intermediates are vital to many biological functions. Coenzyme B12 is a case in point. This organometallic cofactor generates a radical pair upon activation in its dependent enzymes by substrate binding and following photolysis. The resulting cob(ii)alamin/5'-deoxyadenosyl radical pair has unusual magnetic properties that present a challenge to detailed investigation at ambient temperatures. Here, we use femtosecond transient absorption spectroscopy adapted for magnetic field exposure to reveal that the spin dynamics of the B12 radical pair are sufficiently fast for magnetic field effects to be observed on the ultrafast reaction kinetics. Moreover, the large difference in g-values between the radicals of the pair means that effects of the Δg mechanism are observed for the first time for a radical pair system exposed to magnetic fields below 1 T. Spin dynamic simulations allow a value of the cob(ii)alamin radical g-value (2.105) at ambient temperature to be extracted and, because the spin dynamic time scale is faster than the diffusional rotation of the cob(ii)alamin radical, the observed value corresponds to the anisotropic g|| value for this radical.

Photochemical Spin Dynamics of the Vitamin B12 Derivative, Methylcobalamin.

Derivatives of vitamin B12 are six-coordinate cobalt corrinoids found in humans, other animals, and microorganisms. By acting as enzymatic cofactors and photoreceptor chromophores, they serve vital metabolic and photoprotective functions. Depending on the context, the chemical mechanisms of the biologically active derivatives of B12-methylcobalamin (MeCbl) and 5'-deoxyadenosylcobalamin (AdoCbl)-can be very different from one another. The extent to which this chemistry is tuned by the upper axial ligand, however, is not yet clear. Here, we have used a combination of time-resolved Fourier transform-electron paramagnetic resonance (FT-EPR), magnetic field effect experiments, and spin dynamic simulations to reveal that the upper axial ligand alone only results in relatively minor changes to the photochemical spin dynamics of B12. By studying the photolysis of MeCbl, we find that, similar to AdoCbl, the initial (or "geminate") radical pairs (RPs) are born predominantly in the singlet spin state and thus originate from singlet excited-state precursors. This is in contrast to the triplet RPs and precursors proposed previously. Unlike AdoCbl, the extent of geminate recombination is limited following MeCbl photolysis, resulting in significant distortions to the FT-EPR signal caused by polarization from spin-correlated methyl-methyl radical "f-pairs" formed following rapid diffusion. Despite the photophysical mechanism that precedes photolysis of MeCbl showing wavelength dependence, the subsequent spin dynamics appear to be largely independent of excitation wavelength, again similar to AdoCbl. Our data finally provide clarity to what in the literature to date has been a confused and contradictory picture. We conclude that, although the upper axial position of MeCbl and AdoCbl does impact their reactivity to some extent, the remarkable biochemical diversity of these fascinating molecules is most likely a result of tuning by their protein environment.

Flavin Adenine Dinucleotide Photochemistry Is Magnetic Field Sensitive at Physiological pH.

We present time-resolved optical absorption and magnetic field effect data on the photochemistry following blue light excitation of flavin adenine dinucleotide (FAD) in aqueous solution in the pH range 2.3 to 8.0. Effects of closed form conformations of FAD in ground, excited singlet, and radical pair states exhibit significant influence on the observed kinetics and magnetic field dependence and remarkably, magnetic field effects are observed even at physiological pH where the FAD radical pairs are only 75% less magnetic field sensitive than at pH 2.3.

Time-resolved optical absorption microspectroscopy of magnetic field sensitive flavin photochemistry.

The photochemical reactions of blue-light receptor proteins have received much attention due to their very important biological functions. In addition, there is also growing evidence that the one particular class of such proteins, the cryptochromes, may be associated with not only a biological photo-response but also a magneto-response, which may be responsible for the mechanism by which many animals can respond to the weak geomagnetic field. Therefore, there is an important scientific question over whether it is possible to directly observe such photochemical processes, and indeed the effects of weak magnetic fields thereon, taking place both in purified protein samples in vitro and in actual biochemical cells and tissues. For the former samples, the key lies in being able to make sensitive spectroscopic measurements on very small volumes of samples at potentially low protein concentrations, while the latter requires, in addition, spatially resolved measurements on length scales smaller than typical cellular components, i.e., sub-micron resolution. In this work, we discuss a two- and three-color confocal pump-probe microscopic approach to this question which satisfies these requirements and is thus useful for experimental measurements in both cases.

Uncertainty of Integrated Intensity Following Line Profile Fitting of Multiline Spectra.

A novel method of determining the total uncertainty in the integrated intensity of fitted emission lines in multipeaked emission spectra is presented. The proposed method does not require an assumption of the type of line profile to be specified. The absolute difference between a fit and measured spectrum defines the uncertainty of the integrated signal intensity and is subsequently decomposed to determine the uncertainty of each peak in multiline fits. Decomposition relies on tabulating a weighting factor, which describes how each peak contributes to the total integral uncertainty. Applications of this method to quantitative approaches in laser-induced breakdown spectroscopy analysis are described.

MEDEX2015: Greater Sea-Level Fitness Is Associated with Lower Sense of Effort During Himalayan Trekking Without Worse Acute Mountain Sickness.

Rossetti, Gabriella M.K., Jamie H. Macdonald, Matthew Smith, Anna R. Jackson, Nigel Callender, Hannah K. Newcombe, Heather M. Storey, Sebastian Willis, Jojanneke van den Beukel, Jonathan Woodward, James Pollard, Benjamin Wood, Victoria Newton, Jana Virian, Owen Haswell, and Samuel J. Oliver. MEDEX2015: Greater sea-level fitness is associated with lower sense of effort during Himalayan trekking without worse acute mountain sickness. High Alt Med Biol. 18:152-162, 2017.-This study examined the complex relationships of fitness and hypoxic sensitivity with submaximal exercise responses and acute mountain sickness (AMS) at altitude. Determining these relationships is necessary before fitness or hypoxic sensitivity tests can be recommended to appraise individuals' readiness for altitude. Forty-four trekkers (26 men; 18 women; 20-67 years) completed a loaded walking test and a fitness questionnaire in normoxia to measure and estimate sea-level maximal aerobic capacity (maximum oxygen consumption [[Formula: see text]O2max]), respectively. Participants also completed a hypoxic exercise test to determine hypoxic sensitivity (cardiac, ventilatory, and arterial oxygen saturation responses to acute hypoxia, fraction of inspired oxygen [Fio2] = 0.112). One month later, all participants completed a 3-week trek to 5085 m with the same ascent profile. On ascent to 5085 m, ratings of perceived exertion (RPEascent), fatigue by Brunel Mood Scale, and AMS were recorded daily. At 5085 m, RPE during a fixed workload step test (RPEfixed) and step rate during perceptually regulated exercise (STEPRPE35) were recorded. Greater sea-level [Formula: see text]O2max was associated with, and predicted, lower sense of effort (RPEascent; r = -0.43; p < 0.001; RPEfixed; r = -0.69; p < 0.001) and higher step rate (STEPRPE35; r = 0.62; p < 0.01), but not worse AMS (r = 0.13; p = 0.4) or arterial oxygen desaturation (r = 0.07; p = 0.7). Lower RPEascent was also associated with better mood, including less fatigue (r = 0.57; p < 0.001). Hypoxic sensitivity was not associated with, and did not add to the prediction of submaximal exercise responses or AMS. In conclusion, participants with greater sea-level fitness reported less effort during simulated and actual trekking activities, had better mood (less fatigue), and chose a higher step rate during perceptually regulated exercise, but did not suffer from worse AMS or arterial oxygen desaturation. Simple sea-level fitness tests may be used to aid preparation for high-altitude travel.

Electron-Proton Decoupling in Excited-State Hydrogen Atom Transfer in the Gas Phase.

Hydrogen-release by photoexcitation, excited-state-hydrogen-transfer (ESHT), is one of the important photochemical processes that occur in aromatic acids and is responsible for photoprotection of biomolecules. The mechanism is described by conversion of the initial state to a charge-separated state along the O(N)-H bond elongation, leading to dissociation. Thus ESHT is not a simple H-atom transfer in which a proton and a 1s electron move together. Here we show that the electron-transfer and the proton-motion are decoupled in gas-phase ESHT. We monitor electron and proton transfer independently by picosecond time-resolved near-infrared and infrared spectroscopy for isolated phenol-(ammonia)5 , a benchmark molecular cluster. Electron transfer from phenol to ammonia occurred in less than 3 picoseconds, while the overall H-atom transfer took 15 picoseconds. The observed electron-proton decoupling will allow for a deeper understanding and control of of photochemistry in biomolecules.

Optical Absorption and Magnetic Field Effect Based Imaging of Transient Radicals.

Short-lived radicals generated in the photoexcitation of flavin adenine dinucleotide (FAD) in aqueous solution at low pH are detected with high sensitivity and spatial resolution using a newly developed transient optical absorption detection (TOAD) imaging microscope. Radicals can be studied under both flash photolysis and continuous irradiation conditions, providing a means of directly probing potential biological magnetoreception within sub-cellular structures. Direct spatial imaging of magnetic field effects (MFEs) by magnetic intensity modulation (MIM) imaging is demonstrated along with transfer and inversion of the magnetic field sensitivity of the flavin semiquinone radical concentration to that of the ground state of the flavin under strongly pumped reaction cycling conditions. A low field effect (LFE) on the flavin semiquinone-adenine radical pair is resolved for the first time, with important implications for biological magnetoreception through the radical pair mechanism.

Gold coated lanthanide phosphate nanoparticles for targeted alpha generator radiotherapy.

Targeted radiotherapies maximize cytotoxicty to cancer cells. In vivo α-generator targeted radiotherapies can deliver multiple α particles to a receptor site dramatically amplifying the radiation dose delivered to the target. The major challenge with α-generator radiotherapies is that traditional chelating moieties are unable to sequester the radioactive daughters in the bioconjugate which is critical to minimize toxicity to healthy, non-target tissue. The recoil energy of the (225)Ac daughters following α decay will sever any metal-ligand bond used to form the bioconjugate. This work demonstrates that an engineered multilayered nanoparticle-antibody conjugate can deliver multiple α radiations and contain the decay daughters of (225)Ac while targeting biologically relevant receptors in a female BALB/c mouse model. These multi-shell nanoparticles combine the radiation resistance of lanthanide phosphate to contain (225)Ac and its radioactive decay daughters, the magnetic properties of gadolinium phosphate for easy separation, and established gold chemistry for attachment of targeting moieties.

A two-color tunable infrared/vacuum ultraviolet spectrometer for high-resolution spectroscopy of molecules in molecular beams.

We describe here the key technical elements of a two-color tunable IR/VUV photoionization TOF mass spectrometer system which allows a wide-range of high-resolution experiments to be performed on a diverse range of cold molecules and clusters in a molecular beam. In particular we highlight the methods we have applied to provide efficient wavelength separation of the VUV radiation from the longer wavelength components used to generate it and discuss a number of systems that we have studied with the instrument which highlight its flexibility for use in the study of molecular spectroscopy.

LaPO4 nanoparticles doped with actinium-225 that partially sequester daughter radionuclides.

Nanoscale materials have been envisioned as carriers for various therapeutic drugs, including radioisotopes. Inorganic nanoparticles (NPs) are particularly appealing vehicles for targeted radiotherapy because they can package several radioactive atoms into a single carrier and can potentially retain daughter radioisotopes produced by in vivo generators such as actinium-225 ((225)Ac, t(1/2) = 10 d). Decay of this radioisotope to stable bismuth-209 proceeds through a chain of short-lived daughters accompanied by the emission of four α-particles that release >27 MeV of energy. The challenge in realizing the enhanced cytotoxic potential of in vivo generators lies in retaining the daughter nuclei at the therapy site. When (225)Ac is attached to targeting agents via standard chelate conjugation methods, all of the daughter radionuclides are released after the initial α-decay occurs. In this work, (225)Ac was incorporated into lanthanum phosphate NPs to determine whether the radioisotope and its daughters would be retained within the dense mineral lattice. Further, the (225)Ac-doped NPs were conjugated to the monoclonal antibody mAb 201B, which targets mouse lung endothelium through the vasculature, to ascertain the targeting efficacy and in vivo retention of radioisotopes. Standard biodistribution techniques and microSPECT/CT imaging of (225)Ac as well as the daughter radioisotopes showed that the NPs accumulated rapidly in mouse lung after intravenous injection. By showing that excess, competing, uncoupled antibodies or NPs coupled to control mAbs are deposited primarily in the liver and spleen, specific targeting of NP-mAb 201B conjugates was demonstrated. Biodistribution analysis showed that ∼30% of the total injected dose of La((225)Ac)PO(4) NPs accumulated in mouse lungs 1 h postinjection, yielding a value of % ID/g >200. Furthermore, after 24 h, 80% of the (213)Bi daughter produced from (225)Ac decay was retained within the target organ and (213)Bi retention increased to ∼87% at 120 h. In vitro analyses, conducted over a 1 month interval, demonstrated that ∼50% of the daughters were retained within the La((225)Ac)PO(4) NPs at any point over that time frame. Although most of the γ-rays from radionuclides in the (225)Ac decay chain are too energetic to be captured efficiently by SPECT detectors, appropriate energy windows were found that provided dramatic microSPECT images of the NP distribution in vivo. We conclude that La((225)Ac)PO(4)-mAb 201B conjugates can be targeted efficiently to mouse lung while partially retaining daughter products and that targeting can be monitored by biodistribution techniques and microSPECT imaging.

Elucidation of the mechanism by which catecholamine stress hormones liberate iron from the innate immune defense proteins transferrin and lactoferrin.

The ability of catecholamine stress hormones and inotropes to stimulate the growth of infectious bacteria is now well established. A major element of the growth induction process has been shown to involve the catecholamines binding to the high-affinity ferric-iron-binding proteins transferrin (Tf) and lactoferrin, which then enables bacterial acquisition of normally inaccessible sequestered host iron. The nature of the mechanism(s) by which the stress hormones perturb iron binding of these key innate immune defense proteins has not been fully elucidated. The present study employed electron paramagnetic resonance spectroscopy and chemical iron-binding analyses to demonstrate that catecholamine stress hormones form direct complexes with the ferric iron within transferrin and lactoferrin. Moreover, these complexes were shown to result in the reduction of Fe(III) to Fe(II) and the loss of protein-complexed iron. The use of bacterial ferric iron uptake mutants further showed that both the Fe(II) and Fe(III) released from the Tf could be directly used as bacterial nutrient sources. We also analyzed the transferrin-catecholamine interactions in human serum and found that therapeutically relevant concentrations of stress hormones and inotropes could directly affect the iron binding of serum-transferrin so that the normally highly bacteriostatic tissue fluid became significantly more supportive of the growth of bacteria. The relevance of these catecholamine-transferrin/lactoferrin interactions to the infectious disease process is considered.