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Determining the comparative pharmacodynamic equivalence of a non-invasive diagnostic test for patients with adrenal insufficiency using a randomised 2-way crossover trial: the STARLIT-3 study protocol
Get PDFIntroduction
Inadequate production of the essential stress hormone, cortisol, results in adrenal insufficiency (AI), which is associated with significant morbidity and mortality. The current standard diagnostic test for AI is the Short Synacthen Test (SST), but this is both invasive and resource-intensive, involving cannulation and blood sampling. A novel formulation, Nasacthin, has been developed in which the same Active Pharmaceutical Ingredient can be delivered intranasally, with the resultant glucocorticoid levels either measured in serum, or in saliva samples to render the test non-invasive, thus creating a potentially more cost-effective test. The Salivary Test of Adrenal Response to Liquid Intranasal Tetracosactide (STARLIT-3) study aims to determine the diagnostic utility of the test in patients with AI.
Methods and analysis
STARLIT-3 is a randomised 2-way crossover trial which aims to collect data from 32 AI patients allocated to receive both Synacthen and Nasacthin in a random order across two study visits. Paired blood and saliva samples will be collected from participants at baseline, and then at 30 and 60 min after drug administration. Glucocorticoid levels in study samples will be quantified with the aim to determine whether the Nasacthin test is able to correctly diagnose patients with AI by estimating the positive percent agreement with the standard SST using serum cortisol at 30 and 60 min. Data on any reported harms and on the acceptability, usability and tolerability of the Nasacthin test will also be collected.
Ethics and dissemination
The study and subsequent amendments have been reviewed and approved by South Central—Hampshire A Research Ethics Committee. Results will be published in peer-reviewed journals and presented at national and international conferences. Plans for dissemination of results to trial participants will be developed in collaboration with patient and public involvement and engagement groups.
Trial registration number ISRCTN26461337
A ketogenic diet for treatment-resistant depression
Get PDFImportance
Preclinical evidence and case reports suggest potential therapeutic benefits of ketogenic diets (KDs) in the treatment of depression, but evidence from well-controlled randomized clinical trials (RCTs) is lacking.
Objective
To assess the efficacy of a KD compared with a control diet in adults with treatment-resistant depression (TRD).
Design, Setting, and Participants
This RCT was conducted between February 22 and June 15, 2024. Participants aged 18 to 65 years with TRD and a score of 15 or greater on the 9-item Patient Health Questionnaire (PHQ-9) from across the UK were included.
Intervention
Participants were randomized 1:1 to one of two 6-week dietary interventions: (1) KD of prepared foods providing less than 30 g of carbohydrates per day with weekly individual dietetic support or (2) a control (phytochemical [phyto]) diet with vouchers to purchase 1 extra serving of vegetables or fruit and replace saturated fats with unsaturated fats, with equal dietetic support. The last follow-up was at 12 weeks.
Main Outcomes and Measures
The primary outcome was the between-group difference in change in PHQ-9 score from baseline to week 6. Secondary outcomes included PHQ-9 score at 12 weeks, depression remission, anxiety, anhedonia, cognitive impairment, quality of life, and functional outcomes.
Results
The study included 88 participants (mean [SD] age, 42.1 [13.1] years; 61 women [69%]): 44 in the KD group and 44 in the phyto diet group. Depression severity decreased markedly in both groups; the mean (SD) change in PHQ-9 score from baseline to week 6 was −10.5 (7.0) in the KD group and −8.3 (5.1) in the phyto group. The mean between-group differences in PHQ-9 score at 6 and 12 weeks were −2.18 (95% CI, −4.33 to −0.03; P = .05; Cohen d, −0.68; 95% CI −1.35 to −0.01) and −1.85 (95% CI, −4.04 to 0.33; P = .10; Cohen d, −0.58; 95% CI, −1.26 to 0.10), respectively. There were no differences in secondary outcomes between the KD and phyto groups. No serious adverse events occurred.
Conclusions and Relevance
In this RCT, a KD had antidepressant benefits compared with a well-matched control diet at 6 weeks. However, the clinical relevance is uncertain, as the mean effect size compared with the control was modest and not evident in secondary analyses.
Trial Registration
ClinicalTrials.gov Identifier: NCT0609116
Efficient citation screening by weak classifier ensemble*
No full textCitation screening in systematic review is timeconsuming. Machine learning can help semi-automate it but faces obstacles. Each systematic review is a new dataset without initial annotations. Extreme class imbalance against irrelevant studies makes it difficult to select a good subset of samples to train a classifier. The rigid requirement of a (near) total recall of relevant studies demands a careful trade-off between accuracy and recall. This paper pilots a weak classifier ensemble approach to tackle both challenges. The idea of ensembling is employed in two ways. First, multiple cost-effective large language models are applied and averaged to score and rank candidate studies to create a balanced pseudo-labelled training set. Second, different sets of pseudo-negative samples are bootstrapped from low-rank documents and multiple classifiers are trained and combined to make screening decisions. Experiments on 28 systematic reviews demonstrate significant performance improvements brought by the weakly supervised classifier ensemble, which also meets the rigid recall requirement for it to be safely used in practice
Developing an AI-Assisted Tool That Identifies Patients With Multimorbidity and Complex Polypharmacy to Improve the Process of Medication Reviews: Qualitative Interview and Focus Group Study
No full textBackground:
Structured medication reviews (SMRs) are an essential component of medication optimization, especially for patients with multimorbidity and polypharmacy. However, the process remains challenging due to the complexities of patient data, time constraints, and the need for coordination among health care professionals (HCPs). This study explores HCPs’ perspectives on the integration of artificial intelligence (AI)–assisted tools to enhance the SMR process, with a focus on the potential benefits of and barriers to adoption.
Objective:
This study aims to identify the key user requirements for AI-assisted tools to improve the efficiency and effectiveness of SMRs, specifically for patients with multimorbidity, complex polypharmacy, and frailty.
Methods:
A qualitative study was conducted involving focus groups and semistructured interviews with HCPs and patients in the United Kingdom. Participants included physicians, pharmacists, clinical pharmacologists, psychiatrists from primary and secondary care, a policy maker, and patients with multimorbidity. Data were analyzed using a hybrid inductive and deductive thematic analysis approach to identify themes related to AI-assisted tool functionality, workflow integration, user-interface visualization, and usability in the SMR process.
Results:
Four major themes emerged from the analysis: innovative AI potential, optimizing electronic patient record visualization, functionality of the AI tool for SMRs, and facilitators of and barriers to AI tool implementation. HCPs identified the potential of AI to support patient identification and prioritizing those at risk of medication-related harm. AI-assisted tools were viewed as essential in detecting prescribing gaps, drug interactions, and patient risk trajectories over time. Participants emphasized the importance of presenting patient data in an intuitive format, with a patient interface for shared decision-making. Suggestions included color-coding blood results, highlighting critical medication reviews, and providing timelines of patient medical histories. HCPs stressed the need for AI tools to integrate seamlessly with existing electronic patient record systems and provide actionable insights without overwhelming users with excessive notifications or “pop-up” alerts. Factors influencing the uptake of AI-assisted tools included the need for user-friendly design, evidence of tool effectiveness (though some were skeptical about the predictive accuracy of AI models), and addressing concerns around digital exclusion.
Conclusions:
The findings highlight the potential for AI-assisted tools to streamline and optimize the SMR process, particularly for patients with multimorbidity and complex polypharmacy. However, successful implementation depends on addressing concerns related to workflow integration, user acceptance, and evidence of effectiveness. User-centered design is crucial to ensure that AI-assisted tools support HCPs in delivering high-quality, patient-centered care while minimizing cognitive overload and alert fatigue
Safety and efficacy of CRS3123 in adults with a primary episode or first recurrence of Clostridioides difficile infection: a phase 2, randomised, double-blind, multicentre, vancomycin-controlled study
Get PDFBACKGROUND: CRS3123 is a potent inhibitor of protein synthesis in bacteria that express type 1 methionyl-tRNA ligase, resulting in selective antibacterial activity that holds promise as a novel treatment for Clostridioides difficile infection (CDI). The purpose of this study was to evaluate the safety and efficacy of CRS3123 in adults with a primary episode or first recurrence of CDI.
METHODS: This multicentre, randomised, double-blind, vancomycin-controlled, phase 2 study was conducted across 14 enrolling sites in the USA and Canada. Enrolled patients were 18 years or older, with a clinical diagnosis of CDI, including diarrhoea (at least three unformed bowel movements in the 24 h before randomisation) and C difficile toxin A or B, or both, detected in stools. Patients were excluded if they had more than one episode of CDI within the past 3 months or more than two within the past 12 months. Patients were randomly assigned (1:1:1) to receive 10 days of treatment with one of two dose regimens of CRS3123 (200 mg and 400 mg orally twice daily) or oral vancomycin (125 mg orally four times daily). Randomisation used an interactive response technology system and was stratified by history of CDI (first episode vs first recurrence within the past 3-12 months). Masking was maintained by use of matching dummy capsules. Safety was a primary endpoint and was assessed in patients who received at least one dose of study drug. The primary efficacy endpoint was clinical cure (survival and resolution of diarrhoea) at the test-of-cure (TOC) visit (day 12 up to day 15) in the intention-to-treat (ITT) population. The rate of CDI recurrence was a crucial secondary outcome measure assessed at study days 40 and 70 in the microbiological ITT population, which included all patients in the ITT population who tested positively for C difficile toxin at screening or day 1 and who had C difficile isolated in culture. This trial was registered with ClinicalTrials.gov (NCT04781387) and is complete.
FINDINGS: Between May 12, 2021, and April 26, 2024, 58 individuals were assessed for eligibility, 43 of whom were recruited and randomly assigned: 14 (33%) to the CRS3123 200 mg group, 15 (35%) to the CRS3123 400 mg group, and 14 (33%) to the vancomycin group. The mean age of patients was 58·4 years (SD 18·0), 33 (77%) patients were female, and ten (23%) patients were male. 31 (72%) patients had a primary episode of CDI and 12 (28%) patients had a first recurrence of CDI. All patients received at least one dose of the assigned drug. Treatment-emergent adverse events (TEAEs) were mild to moderate in severity and similar across treatment groups. TEAEs considered possibly related to study drug (all grade 1 or 2) were reported in one patient in the CRS3123 200 mg group (dry mouth, asthenia and gastro-oesophageal reflux disease, nausea, vomiting, increased alanine aminotransferase, and increased aspartate aminotransferase), three patients in the CRS3123 400 mg group (one with increases in alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase; one with malaise, nausea, and feeling abnormal; and one with headache); and in no patients in the vancomycin group. The only serious adverse event reported, pneumonia, was in the vancomycin group and was considered unrelated to the study drug. 13 (93%) of 14 patients in the CRS3123 200 mg group, all 15 (100%) patients in the CRS3123 400 mg group, and 13 (93%) of 14 patients in the vancomycin group had clinical cure at the TOC visit. No patient had clinical failure at the TOC visit; two patients (one each in the CRS3123 200 mg and vancomycin groups) had indeterminate responses due to missing data. Recurrence through day 40 occurred in one (7%) of 14 patients in the CRS3123 400 mg group, none of the 13 patients in the CRS3123 200 mg group, and three (23%) of 13 patients in the vancomycin group, and there was an additional recurrence on day 70 in the CRS3123 400 mg group.
INTERPRETATION: Both doses of CRS3123 were deemed safe and well tolerated and showed efficacy similar to vancomycin at the TOC visit, with lower rates of recurrence. Together, these data support further development of CRS3123.
FUNDING: US National Institute of Allergy and Infectious Diseases at the National Institutes of Health, Department of Health and Human Services
Modelling the economic effects of reducing the consumption of unhealthy commodities: an inter-sectoral input-output approach.
Get PDFAIMS: Industry arguments against public health policies that reduce the consumption of unhealthy commodities often include the assertion that the policy will harm the economy by reducing production and costing jobs. However, this argument does not consider that consumers may spend money previously used for unhealthy commodity consumption on other products, benefiting other sectors and potentially offsetting those negative economic consequences. In this study we aimed to estimate the macroeconomic impacts of reducing consumption of alcohol, tobacco, confectionary and gambling, accounting for reallocation of spending from these commodities to alternatives.
METHOD: We developed the open-source Commercial Determinants of Health Input-Output (CDOHIO) model version 1.1.0. CDOHIO models inter-sectoral linkages in the United Kingdom (UK) economy using published input-output tables to estimate the macroeconomic outcomes of changes in the total national consumer expenditure on selected unhealthy commodities and the reallocation of this expenditure to other consumption. We modelled a 10% decrease in total consumer expenditure on (1) alcohol, (2) tobacco, (3) confectionary and (4) gambling, assuming that the reduced expenditure was reallocated entirely to other products. The comparator in each case was no change in expenditure. We analysed six economic outcomes: (i) output (the total value of production in the economy), (ii) tax receipts from employees, (iii) tax receipts from employers, (iv) full-time equivalent employment, (v) total net earnings to individuals, and (vi) Gross Value Added (GVA), which is the primary outcome measure used as a proxy for national Gross Domestic Product.
RESULTS: For tobacco, confectionary and gambling, reduced spending was estimated to yield positive effects across all six measures. The total effect of a 10% reduction in confectionary spending was an increase in GVA of £0.389 billion (0.02%), for reduced spending on tobacco, +£1.859 billion GVA (+0.09%) and for gambling +£1.250 billion GVA (+0.06%). For alcohol, a 10% reduction in spending led to a small negative effect on GVA (-£0.134 billion, -0.01%), which is the net effect of positive effects of reduced spending on off-trade alcohol (+£2.543 billion) and negative effects of reduced spending on on-trade alcohol (-£2.677 billion).
CONCLUSIONS: The potential negative macroeconomic impacts of reducing spending on tobacco, confectionary and gambling in the United Kingdom could be more than mitigated when consumers reallocate money spent on these products to other consumption. This is also the case for off-trade alcohol consumption, but not for on-trade alcohol consumption
Optical Characterisation of Stereolithography-Printed Composites for THz Quasi-Optical Applications
Get PDFThis work investigates the potential of filler materials to enhance the THz transparency of photopolymers compatible with the stereolithography (SLA) 3D printing process. Photopolymers filled with PTFE (~ 30% wt.) and silica (~ 66% wt.) were fabricated via SLA and characterised using a THz time-domain spectroscopy system (THz-TDS). The THz-TDS measurements revealed absorption coefficients of 15.3 cm ‾¹ and 11.7 cm ‾¹ at 1 THz for the PTFE and Silica composites, respectively, with the latter showing a 44.8 % reduction compared with conventional AM photopolymers at the same frequency. This work highlights the potential of filled-photopolymer composites to enable the manufacture of more efficient quasi-optical components via SLA
Retreat and volume loss of two rapidly vanishing Svalbard glaciers since 1938: Elsabreen and Ferdinandbreen, Petuniabukta
No full textThe Arctic is one of the fastest-warming places on Earth. The High Arctic Archipelago of Svalbard contains over 1500 glaciers that have, overall, experienced widespread thinning and recession since the Little Ice Age (LIA; ∼1900 CE), and this recession has accelerated since 1990. Here, we showcase the terminal decline since the end of the LIA of Elsabreen and Ferdinandbreen, two small land-terminating glaciers in Petuniabukta, Dickson Land. We map glacier areal extents using previously published data, aerial photographs and satellite imagery (LIA to 2024) and derive ice volume changes by differencing digital elevation models (1938 to 2023). Both glaciers have lost over 93% of their glacier area since the LIA and over 96% of their ice volume since 1938. By 2024, Elsabreen had reduced to a small glacier remnant with little evidence of ice flow, and Ferdinandbreen had fragmented into several separate ice units and completely detached from its original accumulation areas. Both of these vanishing glaciers merit inclusion on the Global Glacier Casualty List
Tuning and suppression of YIG magnetization dynamics via antiferromagnetic interface coupling
Get PDFThe magnetization dynamics of yttrium iron garnet (Y3Fe5O12, YIG) are key to the operation of spintronic and microwave devices. Here, we report a pathway to manipulate the frequency, damping, and absorption of YIG thin films via interface coupling. The growth on YIG of PtMn, a metallic antiferromagnet, leads to a non-linear resonant frequency vs out-of-plane field dependence and an increased linewidth at low fields. In gadolinium iron garnet/YIG film bilayers, the two films couple antiferromagnetically at low temperatures and there is a strong damping of the magnetization dynamics that is further enhanced at the spin-flop field, suppressing the ferromagnetic resonance signal. When combining both GdIG and PtMn interfaces, we can tune the exponent in the frequency vs field dependence and achieve an almost complete quenching of the magnetization dynamics over a range of fields/frequencies due to non-collinear magnetic order. These effects offer a means to tune and suppress magnetization dynamics for frequency filters, magnonics, spin pumping, and other applications
Electrochemical Insight into the Copper Redox Chemistry and H2O2 and O2 Reducing Capability of Two AA10 Lytic Polysaccharide Monooxygenases
Get PDFLytic polysaccharide monooxygenases ([L]PMOs) are copper-containing enzymes that catalyse cleavage of the glycosidic bond, a process central to microbial biomass degradation. Here, we describe electrochemical methods used to investigate the Cu2+/1+ redox chemistry and the polysaccharide-free catalytic activity of two AA10 LPMOs: CjAA10B from Cellvibrio japonicus and CfAA10 from Cellulomonas fimi. Immobilisation of these enzymes on the surface of a graphite electrode allows for direct electrochemical measurements of Cu2+/1+ redox cycling as well as the ability of both LPMOs to reduce H2O2 vs O2. These measurements can be advantageous when compared to biological dye assays as they provide direct kinetic measurements and allow for investigation over a wider range of environmental conditions. Values of kcat and KM- are reported for H2O2 and O2 reduction by CjAA10B and CfAA10 from pH 5–7, with CfAA10 consistently outperforming CjAA10B. Both enzymes perform faster catalysis with H2O2 but when comparing the affinity-coupled specificity constant (kcat/KM), the LPMOs perform similarly with both H2O2 and O2, suggesting both substrates are viable. We also note an increase in redox signals as pH is decreased that correlates with EPR data suggesting a second species is formed <pH 5, postulated to occur due to the protonation of a glutamate residue (pKa ∼ 4.6). The increase in signal size with decreasing pH that is seen for the non-catalytic Cu2+/1+ transition is interpreted in light of an increasing proportion of electroactive species at low pH; such a change in activity with pH is notably not observed in the presence of substrate (H2O2 or O2). This suggests that substrate binding modulates the active site, disrupting the effect of protonation. These findings establish electrochemistry as a powerful tool for probing LPMO activity
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