The use of pembrolizumab monotherapy for the management of head and neck squamous cell carcinoma (HNSCC) in the UK.

Pembrolizumab has received approval in the UK as first-line monotherapy for recurrent and/or metastatic HNSCC (R/M HNSCC) following the results of the KEYNOTE-048 trial, which demonstrated a longer overall survival (OS) in comparison to the EXTREME chemotherapy regimen in patients with a combined positive score (CPS) ≥1. In this article, we provide retrospective real-world data on the role of pembrolizumab monotherapy as first-line systemic therapy for HNSCC across 18 centers in the UK from March 20, 2020 to May 31, 2021. 211 patients were included, and in the efficacy analysis, the objective response rate (ORR) was 24.7%, the median progression-free survival (PFS) was 4.8 months (95% confidence interval [CI]: 3.6-6.1), and the median OS was 10.8 months (95% CI 9.0-12.5). Pembrolizumab monotherapy was well tolerated, with 18 patients having to stop treatment owing to immune-related adverse events (irAEs). 53 patients proceeded to second-line treatment with a median PFS2 of 10.2 months (95% CI: 8.8-11.5). Moreover, patients with documented irAEs had a statistically significant longer median PFS (11.3 vs. 3.3 months; log-rank p value = <.001) and median OS (18.8 vs. 8.9 months; log-rank p value <.001). The efficacy and safety of pembrolizumab first-line monotherapy for HNSCC has been validated using real-world data.

A machine learning system to optimise triage in an adult ophthalmic emergency department: a model development and validation study.

Background: A substantial proportion of attendances to ophthalmic emergency departments are for non-urgent presentations. We developed and evaluated a machine learning system (DemDx Ophthalmology Triage System: DOTS) to optimise triage, with the aim of reducing inappropriate emergency attendances and streamlining case referral when necessary. Methods: DOTS was built using retrospective tabular data from 11,315 attendances between July 1st, 2021, to June 15th, 2022 at Moorfields Eye Hospital Emergency Department (MEH) in London, UK. Demographic and clinical features were used as inputs and a triage recommendation was given ("see immediately", "see within a week", or "see electively"). DOTS was validated temporally and compared with triage nurses' performance (1269 attendances at MEH) and validated externally (761 attendances at the Federal University of Minas Gerais - UFMG, Brazil). It was also tested for biases and robustness to variations in disease incidences. All attendances from patients aged at least 18 years with at least one confirmed diagnosis were included in the study. Findings: For identifying ophthalmic emergency attendances, on temporal validation, DOTS had a sensitivity of 94.5% [95% CI 92.3-96.1] and a specificity of 42.4% [38.8-46.1]. For comparison within the same dataset, triage nurses had a sensitivity of 96.4% [94.5-97.7] and a specificity of 25.1% [22.0-28.5]. On external validation at UFMG, DOTS had a sensitivity of 95.2% [92.5-97.0] and a specificity of 32.2% [27.4-37.0]. In simulated scenarios with varying disease incidences, the sensitivity was ≥92.2% and the specificity was ≥36.8%. No differences in sensitivity were found in subgroups of index of multiple deprivation, but the specificity was higher for Q2 when compared to Q4 (Q4 is less deprived than Q2). Interpretation: At MEH, DOTS had similar sensitivity to triage nurses in determining attendance priority; however, with a specificity of 17.3% higher, DOTS resulted in lower rates of patients triaged to be seen immediately at emergency. DOTS showed consistent performance in temporal and external validation, in social-demographic subgroups and was robust to varying relative disease incidences. Further trials are necessary to validate these findings. This system will be prospectively evaluated, considering human-computer interaction, in a clinical trial. Funding: The Artificial Intelligence in Health and Care Award (AI_AWARD01671) of the NHS AI Lab under National Institute for Health and Care Research (NIHR) and the Accelerated Access Collaborative (AAC).

Usability of an artificially intelligence-powered triage platform for adult ophthalmic emergencies: a mixed methods study.

There is growing demand for emergency-based eyecare services where the majority of those attending do not require urgent ophthalmic management. The Royal College of Ophthalmologists have recommended upskilling and supporting of allied health professionals to support eyecare delivery, where machine learning algorithms could help. A mixed methods study was conducted to evaluate the usability of an artificial intelligence (AI) powered online triage platform for ophthalmology. The interface, usability, safety and acceptability were investigated using a Think Aloud interview and usability questionnaires. Twenty participants who actively examine patients in ophthalmic triage within a tertiary eye centre or primary care setting completed the interview and questionnaires. 90% or more of participants found the platform easy to use, reflected their triage process and were able to interpret the triage outcome, 85% found it safe to use and 95% felt the processing time was fast. A quarter of clinicians reported that they have experienced some uncertainty when triaging in their career and were unsure of using AI, after this study 95% of clinicians were willing to use the platform in their clinical workflow. This study showed the platform interface was acceptable and usable for clinicians actively working in ophthalmic emergency triage.

Intrinsic capacity of older people in the community using WHO Integrated Care for Older People (ICOPE) framework: a cross-sectional study.

BACKGROUND: The World Health Organization (WHO) published the Integrated Care for Older People (ICOPE) framework to guide assessing and promoting intrinsic capacity of older adults. This study, adopting the WHO ICOPE framework, assessed the intrinsic capacity impairment and investigated the relationship among intrinsic capacity, social engagement, and self-care capacity on performing activities of daily living. It also assessed the sensitivity of the initial brief screening and the detailed full assessment. METHODS: This is a cross-sectional study conducted in 11 community centers in Hong Kong. Intrinsic capacity was assessed in two steps identical to WHO ICOPE handbook: using WHO ICOPE brief screening tool (step 1) and detailed full assessment (step 2) to assess the intrinsic capacity domains of locomotion, cognition, vitality, psychological well-being, and sensory capacity (hearing and vision). Structural equational modeling analysis was used to examine the relationship among intrinsic capacity, social engagement, and self-care capacity, and the mediating role of intrinsic capacity in the relationships. RESULTS: A total of 304 older adults with a mean age 76.73 (SD = 7.25) years participated in WHO ICOPE Step 1 brief screening, and 221 participants (72.7%) showed intrinsic capacity impairment. After completing Step 2 full assessment, 202 participants (66.4%) had one or more impaired intrinsic capacity domains. The overall sensitivity and specificity of the screening tool were 95% and 57.6% respectively, whereas the sensitivity of each domain ranged from 74.7% to 100%. The percentage of impairment in locomotion (117, 39.8%), cognition (75, 25.5%), psychological well-being (34, 11.6%), vision (75, 24.7%), hearing capacity (82, 27.9%), and vitality (8, 2.7%). People in younger old age (ß = -0.29, p < 0.001), with more education (ß = 0.26, p < 0.001), and absence of hypertension (ß = -0.11, p < 0.05) were more likely to have better intrinsic capacity. Intrinsic capacity was positively associated with self-care capacity in performing activities of daily living (ß = 0.21, p < 0.001) and social engagement (ß = 0.31, p < 0.001). CONCLUSIONS: The ICOPE screening tool is a sensitive instrument to detect intrinsic capacity impairment among community-dwelling older adults and it does not demand substantial workforce; its use is worthy to be supported. The intrinsic capacity impairment in community-dwelling older adults are prevalent, in particular, in locomotor and cognitive capacity. Actions should be taken to slow or prevent the impairment, support self-care and social engagement in old age.

Sustainable low-field cardiovascular magnetic resonance in changing healthcare systems.

Cardiovascular disease continues to be a major burden facing healthcare systems worldwide. In the developed world, cardiovascular magnetic resonance (CMR) is a well-established non-invasive imaging modality in the diagnosis of cardiovascular disease. However, there is significant global inequality in availability and access to CMR due to its high cost, technical demands as well as existing disparities in healthcare and technical infrastructures across high-income and low-income countries. Recent renewed interest in low-field CMR has been spurred by the clinical need to provide sustainable imaging technology capable of yielding diagnosticquality images whilst also being tailored to the local populations and healthcare ecosystems. This review aims to evaluate the technical, practical and cost considerations of low field CMR whilst also exploring the key barriers to implementing sustainable MRI in both the developing and developed world.

Application of diffusion-weighted whole-body MRI for response monitoring in multiple myeloma after chemotherapy: a systematic review and meta-analysis.

OBJECTIVE: Myeloma Response Assessment and Diagnosis System recently published provides a framework for the standardised interpretation of DW-WBMRI in response assessment of multiple myeloma (MM) based on expert opinion. However, there is a lack of meta-analysis providing higher-level evidence to support the recommendations. In addition, some disagreement exists in the literature regarding the effect of timing and lesion subtypes on apparent diffusion coefficient (ADC) value changes post-treatment. METHOD: Medline, Cochrane and Embase were searched from inception to 20th July 2021, using terms reflecting multiple myeloma and DW-WBMRI. Using PRISMA reporting guidelines, data were extracted by two investigators. Quality was assessed by the Quality Assessment of Diagnostic Accuracy Studies-2 method. RESULTS: Of the 74 papers screened, 10 studies were included comprising 259 patients (127 males and 102 females) and 1744 reported lesions. Responders showed a significant absolute ADC change of 0.21×10-3 mm/s2 (95% CI, 0.01-0.41) with little evidence of heterogeneity (Cochran Q, p = 0.12, I2 = 45%) or publication bias (p = 0.737). Non-responders did not show a significant absolute difference in ADC (0.06 ×10-3 mm/s2, 95% CI, -0.07 to 0.19). A percentage ADC increase of 34.78% (95% CI, 10.75-58.81) was observed in responders. Meta-regression showed an inverse trend between ADC increases and time since chemotherapy initiation which did not reach statistical significance (R2 = 20.46, p = 0.282). CONCLUSIONS: This meta-analysis supports the use of the DW-WBMRI as an imaging biomarker for response assessment. More evidence is needed to further characterise ADC changes by lesion subtypes over time. KEY POINTS: • In multiple myeloma patients who received chemotherapy, responders have a significant absolute increase in ADC values that is not seen in non-responders. • A 35% increase in ADC from baseline values is found to classify response post-induction chemotherapy which corroborates with expert opinion from the Myeloma Response Assessment and Diagnosis System. • More evidence is needed to further characterise ADC changes by lesion subtypes over time after induction of therapy.

Intraosseous Type 2 Median Nerve Entrapment After Posterior Elbow Dislocation Diagnosed on Ultrasound With MRI and Surgical Correlation.

Median nerve entrapment is a rare complication of posterior elbow dislocation and medial epicondyle fracture. In the event of delayed diagnosis, this injury pattern may result in significant and sometimes irreversible nerve damage. As such, a high degree of clinical suspicion and early imaging is indicated in patients with persistent nerve deficits following reduction of elbow dislocation. Here, a case of intraosseous type 2 median nerve entrapment that was diagnosed on ultrasound in an eight-year-old patient following ulnohumeral dislocation is discussed. This article reviews the key imaging findings of median nerve entrapment and discusses the subsequent MRI and surgical findings of this rare condition.

Making Nature Explicit in Children's Drawings of Wellbeing and Happy Spaces.

Previous research on children's wellbeing indicators has focused extensively on adults', rather than children's perspectives, despite there being a broad consensus that children's conceptualisations differ significantly from adults'. In response, this study aimed to explore what constitutes children's wellbeing through their drawings and discussions. Ninety-one seven and eight-year old children from two primary schools in areas of relatively high deprivation in eastern England participated in this study. We identified indicators of wellbeing that were made explicit in children's drawings, such as the need for safety, happiness and positive relationships, but also indicators that remained rather implicit, such as the environment and nature. The drawings in particular illustrated that children's perceptions of wellbeing were subject to the affordances of their favourite spaces for emotional, mental physical and material wellbeing. Access to nature and outdoor spaces was interconnected with all these affordances. We analysed these findings through the theoretical lenses of positive psychology, self-actualisation, social mentality and the human-nature relationship. We argue that making nature explicit, and restoring the interconnectedness between the arts and nature in the current literature, should be a key priority for future research and practice on children's wellbeing indicators.

Dispositional optimism and cognitive functioning following traumatic brain injury.

Objective: The association of dispositional optimism with health-related factors has been well established in several clinical populations, but little is known about the role of optimism in recovery after traumatic brain injury (TBI). Given the high prevalence of cognitive complaints after TBI, the present study examined the association between optimism and cognitive functioning after TBI. Methods: 171 individuals with complicated mild, moderate or severe TBI completed a series of questionnaires via structured interview and self-report, including a self-report assessment of dispositional optimism, the revised Life Orientation Test (LOT-R), and an objective assessment of cognition, the Brief Test of Adult Cognition by Telephone (BTACT). Multiple hierarchical regression analysis was conducted to examine the relationships between optimism and cognitive functioning. Results: Dispositional optimism was significantly and positively associated with post-TBI cognitive functioning after controlling for the effects of age, race, injury severity, health status, and positive and negative affect. Conclusion: Dispositional optimism may promote higher levels of cognitive functioning in people who sustained a TBI. Research is warranted to examine whether interventions that promote optimism in clinical and social encounters can enhance cognitive recovery in individuals with TBI.

Membrane fusion correlates with surface charge in exocytic vesicles.

Stimulation of gastric parietal cells results in exocytic recruitment of the proton pump (H(+),K(+)-ATPase) from a pool of intracellular membranes (tubulovesicles) to the apical plasma membrane. We have previously reconstituted a step in this process, the homotypic fusion of tubulovesicles, and shown that they also fuse with liposomes in a protein-dependent manner [Duman, J. G., Singh, G., Lee, G. Y., Machen, T. E., and Forte, J. G. (2002) Traffic 3, 203-17]. Further, the lipid composition of the liposomes affects their ability to undergo fusion with tubulovesicles. In the present study, we investigated the lipid requirements for tubulovesicular membrane fusion using a fluorescent probe relaxation assay as well as transfer of protein between tubulovesicles and liposomes of defined composition. Initially, we tested the ability of tubulovesicles to undergo fusion with a panel of synthetic phosphatidylcholine-based liposomes containing a variety of common membrane lipids of various shapes and charges. We found that anionic lipids such as phosphatidylserine, phosphatidic acid, and phosphoinositides were best able to enhance tubulovesicle-liposome fusion and that they did it in a dose-dependent, apparently saturable manner. Next, we altered the lipid compositions of actual tubulovesicles and observed that addition of anionic lipids was able to enhance tubulovesicle-tubulovesicle fusion in vitro; thus, we hypothesized that the charge imparted by the lipids, per se, was responsible for the enhancement of membrane fusion. Accordingly, addition of negative charges to one of two pools of tubulovesicles in a fusion assay using anionic detergents increased membrane fusion; whereas, addition of positively charged cationic detergent decreased membrane fusion and could be used to back-titrate the anionic effects. Surprisingly, when both pools of fusing membranes were loaded with anionic detergents, fusion was markedly increased. The ability of anionic charges to enhance fusion was diminished as the ionic strength of the fusion medium was increased, suggesting that the mechanism of fusion enhancement depends on the surface charge of the membranes. Finally, the fusion reaction was highly dependent on temperature, and anionic charge appears to lower the activation energy of the fusion reaction. Taken together, these data suggest that (1) tubulovesicular fusion is enhanced by an increase in membrane surface negative charge associated with a lower activation energy and (2) neutralization or reversal of the surface charge prevents tubulovesicular fusion.

Effects of vitamin E and pinoline on retinal lipid peroxidation.

BACKGROUND: Pinoline is a pineal indoleamine naturally found in the retina. This study compared the effects of pinoline and vitamin E on the copper (I)-induced retinal lipid peroxidation (LPO). METHODS: Porcine retinal homogenates were mixed with 120 micro M copper (I) solution. The mixtures were co-incubated with various concentrations of pinoline or trolox (water-soluble vitamin E analogue) at 37 degrees Centigrade for 60 minutes. The amounts of malondialdehyde (MDA) and protein were assayed to quantify the LPO. RESULTS: Copper (I) ions significantly increased the MDA concentration in the retinal homogenates (p < 0.0007). Both pinoline and trolox significantly suppressed MDA in a dose-dependent manner (p < 0.0001) and their effects were significantly different (p = 0.004). The concentrations that inhibited 50 per cent of LPO were 0.24 mM and 0.68 mM for pinoline and trolox, respectively. DISCUSSION: Pinoline suppressed the LPO at a potency of 2.8 times compared with trolox. The results support an anti-oxidative role for pinoline in the retina. Further study is required to characterise the pharmacological potency of pinoline in vivo.