The burden of diabetes-associated multiple long-term conditions on years of life spent and lost.

Diabetes mellitus is a central driver of multiple long-term conditions (MLTCs), but population-based studies have not clearly characterized the burden across the life course. We estimated the age of onset, years of life spent and loss associated with diabetes-related MLTCs among 46 million English adults. We found that morbidity patterns extend beyond classic diabetes complications and accelerate the onset of severe MLTCs by 20 years earlier in life in women and 15 years earlier in men. By the age of 50 years, one-third of those with diabetes have at least three conditions, spend >20 years with them and die 11 years earlier than the general population. Each additional condition at the age of 50 years is associated with four fewer years of life. Hypertension, depression, cancer and coronary heart disease contribute heavily to MLTCs in older age and create the greatest community-level burden on years spent (813 to 3,908 years per 1,000 individuals) and lost (900 to 1,417 years per 1,000 individuals). However, in younger adulthood, depression, severe mental illness, learning disabilities, alcohol dependence and asthma have larger roles, and when they occur, all except alcohol dependence were associated with long periods of life spent (11-14 years) and all except asthma associated with many years of life lost (11-15 years). These findings provide a baseline for population monitoring and underscore the need to prioritize effective prevention and management approaches.

The Use of Online Consultation Systems and Patient Experience of Primary Care: Cross-Sectional Analysis Using the General Practice Patient Survey.

BACKGROUND: NHS England encourages the use of online consultation (OC) systems alongside traditional access methods for patients to contact their general practice online and for practices to manage workflow. Access is a key driver of patients' primary care experience. The use of online technology and patient experience vary by sociodemographic characteristics. OBJECTIVE: This study aims to assess the association between OC system use and patient experience of primary care in English general practice and how that varies by OC system model and practice sociodemographic characteristics (rurality, deprivation, age, and ethnicity). METHODS: We categorized practices as "low-use" or "high-use" according to the volume of patient-initiated contacts made via the OC system. We considered practices using one of 2 OC systems with distinct designs and implementation models-shorter "free text" input with an embedded single workflow OC system (FT practices) and longer "mixed text" input with variation in implemented workflow OC system (MT practices). We used 2022 General Practice Patient Survey data to capture 4 dimensions of patient experience-overall experience, experience of making an appointment, continuity of care, and use of self-care before making an appointment. We used logistic regression at the practice level to explore the association between OC system use and patient experience, including interaction terms to assess sociodemographic variation. RESULTS: We included 287,194 responses from 2423 MT and 170 FT practices. The proportions of patients reporting positive experiences at MT and FT practices were similar or better than practices nationally, except at high-use MT practices. At high-use MT practices, patients were 19.8% (odds ratio [OR] 0.802, 95% CI 0.782-0.823) less likely to report a good overall experience; 24.5% (OR 0.755, 95% CI 0.738-0.773) less likely to report a good experience of making an appointment; and 18.9% (OR 0.811, 95% CI 0.792-0.83) less likely to see their preferred general practitioner; but 27.8% (OR 1.278, 95% CI 1.249-1.308) more likely to use self-care, compared with low-use MT practices. Opposite trends were seen at FT practices. Sociodemographic inequalities in patient experience were generally lower at high-use than low-use practices; for example, gaps in overall experience between practices with the most and fewest White patients decreased by 2.7 percentage points at MT practices and 6.4 percentage points at FT practices. Trends suggested greater improvements in experience for traditionally underserved groups-patients from urban and deprived areas, younger patients, and non-White patients. CONCLUSIONS: An OC system with shorter free text input and an integrated single workflow can enhance patient experience and reduce sociodemographic inequalities. Variation in patient experience between practices with different sociodemographic characteristics and OC systems underscores the importance of tailored design and implementation. Generalizing results across different OC systems is difficult due to variations in how they are integrated into practice workflows and communicated to patients.

Antibiotic prescribing in remote versus face-to-face consultations for acute respiratory infections in primary care in England: an observational study using target maximum likelihood estimation.

Background: The COVID-19 pandemic has led to an ongoing increase in the use of remote consultations in general practice in England. Although the evidence is limited, there are concerns that the increase in remote consultations could lead to more antibiotic prescribing. Methods: In this cohort study, we used patient-level primary care data from the Clinical Practice Research Datalink to estimate the association between consultation mode (remote versus face-to-face) and antibiotic prescribing in England for acute respiratory infections (ARI) between April 2021 and March 2022. Eligibility criteria were applied at both practice-level and patient-level. 400 practices in England were sampled at random and then 600,000 patients were randomly sampled from the eligible patients (whose sex was recorded). Consultations for acute respiratory infections were identified. All antibiotic prescriptions were included, with the exception of antituberculosis drugs and antileprotic drugs, as identified through chapter 5.1 of the British National Formulary. The CPRD Aurum data was linked to the COVID-19 ONS infection survey by region. All analyses were done at the individual level. Repeated consultations from the same patient within 7 days were grouped together. We used targeted maximum likelihood estimation, a causal machine learning method with adjustment for infection type and patient-level, clinician-level and practice-level factors. Findings: There were 45,997 ARI consultations (34,555 unique patients) within the study period, of which 28,127 were remote and 17,870 were face-to-face. For children, 48% of consultations were remote and, for adults, 66% were remote. For children, 42% of remote and 43% of face-to-face consultations led to an antibiotic prescription; the equivalent values for adults were 52% and 42%, respectively. After adjustment with TMLE, adults with a remote consultation had 23% (odds ratio [OR] 1.23, 95% CI: 1.18-1.29) higher chance of being prescribed antibiotics than if they had been seen face-to-face. We found no significant association between consultation mode and antibiotic prescribing in children (OR 1.04 95% CI: 0.98-1.11). Interpretation: The higher rates of antibiotic prescribing in remote consultations for adults are cause for concern. We see no significant difference in antibiotic prescribing between consultation mode for children. These findings should inform antimicrobial stewardship activities for health-care professionals and policy makers. Future research should examine differences in guideline-compliance between remote and face-to-face consultations to understand the factors driving antibiotic prescribing in different consultation modes. Funding: None.

How is primary care access changing? A retrospective, repeated cross-sectional study of patient-initiated demand at general practices in England using a modern access model, 2019-2022.

OBJECTIVES: To explore trends in patient-initiated requests for general practice services and the association between patient characteristics including demographics, preferences for care and clinical needs and modes of patient contact (online vs telephone), and care delivery (face-to-face vs remote) at practices using a modern access model. DESIGN: Retrospective repeated cross-sectional study spanning March 2019 to February 2022. SETTING: General practices in England using the askmyGP online consultation system to implement a modern general practice access model using digital and non-digital (multimodal) access pathways and digitally supported triage to manage patient-initiated requests. PARTICIPANTS: 10 435 465 patient-initiated requests from 1 488 865 patients at 154 practices. RESULTS: Most requests were initiated online (72.1% in 2021/2022) rather than by telephone. Online users were likely to be female, younger than 45 years, asking about existing medical problems, had used the system before and frequent attenders (familiar patients). During the pandemic, request rates for face-to-face consultations fell while those for telephone consultations and online messages increased, with telephone consultations being most popular (53.8% in 2021/2022). Video was seldom requested. More than 60% of requests were consistently delivered in the mode requested. Face-to-face consultations were more likely to be used for the youngest and oldest patients, new medical problems, non-frequent attenders (unfamiliar patients) and those who requested a face-to-face consultation. Over the course of the study, request rates for patients aged over 44 years increased, for example, by 15.4% (p<0.01) for patients aged over 74 years. Rates for younger patients decreased by 32.6% (p<0.001) in 2020/2021, compared with 2019/2020, before recovering to prepandemic levels in 2021/2022. CONCLUSIONS: Demand patterns shed light on the characteristics of patients making requests for general practice services and the composition of the care backlog with implications for policy and practice. A modern general practice access model can be used effectively to manage patient-initiated demand.

Strain distribution on a finger link: a static simulation study.

Functional prosthetics hands which have the ability to help amputees perform tasks in daily life have been developed over many years. These hands need a control system which is fed information from sensors mounted on a prosthetic hand and human-machine interface. A variety of sensors therefore been developed for the prosthetic hand to measure fingertip force, joint angle (position), object slip, texture and temperature. However, most of the strain/stress sensors are attached to the fingertip. In this paper, the potential positions for strain sensors on the side of the finger link of the prosthetic hand are investigated that, in the future, will allow for force control in a lateral or key grip. With modified links of a Southampton Hand, some promising positions for strain sensors have been determined. On some of the links, the strain sensor can be used as an indicator to show the angle of the finger during a curling operation.

Following the patient's orders? Recommending vs. offering choice in neurology outpatient consultations.

The UK's Royal College of Surgeons (2016) has argued that health professionals must replace a 'paternalistic' approach to consent with 'informed choice'. We engage with these guidelines through analysis of neurology consultations in two UK-based neuroscience centres, where informed choice has been advocated for over a decade. Based on 223 recorded consultations and related questionnaire data (collected in 2012), we used conversation analysis (CA) to identify two practices for offering choice: patient view elicitors (PVEs) and option-lists. This paper reports further, mixed-methods analyses, combining CA with statistical techniques to compare the 'choice' practices with recommendations. Recommendations were overwhelmingly more common. There was little evidence that patient demographics determined whether choice was offered. Instead, decisional practices were associated with a range of clinical considerations. There was also evidence that individual neurologists tended to have a 'style', making it partly a matter of chance which decisional practice(s) patients encountered. This variability matters for the perception of choice: neurologists and patients were more likely to agree a choice had been offered if a PVE or option-list was used. It also matters for the outcome of the decision-making process: while recommendations nearly always ended in agreement to undertake the proffered course of action, option-lists and PVEs did so only about two-thirds of the time. While the direction of causality is unknown, this may indicate that patients are better enabled to refuse things they don't want when neurologists avoid recommending. We argue that our findings imply that neurologists tend to view choice as risky - in that the patient might make the 'wrong' choice - but that the inter-individual variation indicates that greater use of the more participatory practices is possible.

PARTICIPATORY DESIGN OF PEDIATRIC UPPER LIMB PROSTHESES: QUALITATIVE METHODS AND PROTOTYPING.

OBJECTIVES: The study aims to develop an understanding of the views of children and adolescents, parents, and professionals on upper limb prosthetic devices to develop and improve device design. Previous research has found that children are dissatisfied with prostheses but has relied heavily on parent proxy reports and quantitative measures (such as questionnaires) to explore their views. METHODS: Thirty-four participants (eight children aged 8-15 years with upper limb difference, nine parents, eight prosthetists, and nine occupational therapists) contributed to the development of new devices through the BRIDGE methodology of participatory design, using focus groups and interviews. RESULTS: The study identified areas for improving prostheses from the perspective of children and adolescents, developed prototypes based on these and gained feedback on the prototypes from the children and other stakeholders (parents and professionals) of paediatric upper limb prostheses. Future device development needs to focus on ease of use, versatility, appearance, and safety. CONCLUSIONS: This study has demonstrated that children and adolescents can and should be involved as equal partners in the development of daily living equipment and that rapid prototyping (three-dimensional printing or additive manufacturing), used within a participatory design framework, can be a useful tool for facilitating this.

Dangerous girls and cheating boys: Zulu-speaking disabled young peoples' constructs of heterosexual relationships in Kwazulu-Natal, South Africa.

Across South Africa there is a growing body of work that explores gender dynamics in heterosexual relationships between young people aged 15-24 years. This is mainly influenced by the high prevalence of HIV and the incidence of intimate partner violence in this age group. Most studies to date have been based upon non-disabled young people, with limited focus on young disabled people. In an attempt to address this gap, this paper describes findings from a study conducted with 22 Zulu-speaking young people with visual and physical disabilities in KwaZulu-Natal. Throughout the findings, young disabled participants appeared to downplay their disability with respect to intimate relationships and accentuated the interweaving of complementary and contentious discourses of gender and cultural identity. Taking cognisance of the intersectionality of gender and cultural discourses, the paper extend constructs of disabled sexualities beyond an exclusive gaze on disability in the South African context.

Neurologists can identify diagnostic linguistic features during routine seizure clinic interactions: results of a one-day teaching intervention.

The diagnostic distinction between epilepsy and psychogenic nonepileptic seizures (PNES) can be challenging. Previous studies have demonstrated that experts in conversation analysis can identify linguistic and interactional features in transcripts and recordings of interviews with patients that reliably distinguish between epilepsy and PNES. In this study, ten senior neurology trainees took part in a one-day intervention workshop about linguistic and interactional differences in the conversation behavior of patients with epilepsy and those with PNES. Participants were familiarized with a 12-item questionnaire designed to capture their conversational observations immediately after talking to a patient with seizures. After the intervention, 55 initial outpatient visits of patients referred to seizure clinics were video and audio recorded. All medical diagnoses were confirmed two years after initial presentation on the basis of a chart review (including MRI and EEG findings) by a fully trained epilepsy expert. Postvisit questionnaires relating to patients confirmed to have epilepsy (n=20) or PNES (n=13) were analyzed. Doctors' mean responses to 6 of the 12 questions about linguistic and interactional observations differed significantly between the groups with epilepsy and PNES. Receiver operating curve analysis showed that a summation scale based on items demonstrating significant between-group differences correctly classified 81.8% of patients as having epilepsy or PNES. This study shows that a brief Conversation Analytic teaching intervention can enable neurologists to identify linguistic and interactional features supporting the differentiation of epilepsy and PNES as they take their patients' history in routine seizure clinic consultations, potentially improving diagnostic accuracy.

Different modes of variation for each BG lineage suggest different functions.

Mammalian butyrophilins have various important functions, one for lipid binding but others as ligands for co-inhibition of αß T cells or for stimulation of γδ T cells in the immune system. The chicken BG homologues are dimers, with extracellular immunoglobulin variable (V) domains joined by cysteines in the loop equivalent to complementarity-determining region 1 (CDR1). BG genes are found in three genomic locations: BG0 on chromosome 2, BG1 in the classical MHC (the BF-BL region) and many BG genes in the BG region just outside the MHC. Here, we show that BG0 is virtually monomorphic, suggesting housekeeping function(s) consonant with the ubiquitous tissue distribution. BG1 has allelic polymorphism but minimal sequence diversity, with the few polymorphic residues at the interface of the two V domains, suggesting that BG1 is recognized by receptors in a conserved fashion. Any phenotypic variation should be due to the intracellular region, with differential exon usage between alleles. BG genes in the BG region can generate diversity by exchange of sequence cassettes located in loops equivalent to CDR1 and CDR2, consonant with recognition of many ligands or antigens for immune defence. Unlike the mammalian butyrophilins, there are at least three modes by which BG genes evolve.

Do patients want choice? An observational study of neurology consultations.

OBJECTIVES: To determine how often patients are given choice in neurology outpatient consultations and whether choice is associated with greater patient satisfaction. METHODS: Prospective study in outpatient clinics in two United Kingdom centres. Interactions between 14 neurologists and 223 patients were studied. Participating doctors and patients completed post-appointment questionnaires asking whether choice had been offered/perceived. Patients completed the Medical Interview Satisfaction Scale 21 (MISS-21). RESULTS: Choice was reported after most encounters (patients 71.8%, neurologists 67.9%). Patients and Neurologists failed to agree about whether choice was offered after 32% of consultations. Choice was not associated with increased patient satisfaction. In fact, satisfaction was greater when no choice had been offered (p=0.05). Satisfaction scores were also greater when doctors were more certain about the diagnosis and when symptoms were considered explained by a medical condition (p≤0.001). CONCLUSIONS: Choice featured in the majority of clinical interactions but clinicians and patients often disagreed whether this was the case. Choice was not associated with greater patient satisfaction. PRACTICE IMPLICATIONS: Clinicians need to be very explicit if they want patients to know that they are being given choices. Choice is not necessarily valued by patients in all clinical interactions.

Hand movements classification for myoelectric control system using adaptive resonance theory.

This research proposes an exploratory study of a simple, accurate, and computationally efficient movement classification technique for prosthetic hand application. Surface myoelectric signals were acquired from the four muscles, namely, flexor carpi ulnaris, extensor carpi radialis, biceps brachii, and triceps brachii, of four normal-limb subjects. The signals were segmented, and the features were extracted with a new combined time-domain feature extraction method. Fuzzy C-means clustering method and scatter plot were used to evaluate the performance of the proposed multi-feature versus Hudgins' multi-feature. The movements were classified with a hybrid Adaptive Resonance Theory-based neural network. Comparative results indicate that the proposed hybrid classifier not only has good classification accuracy (89.09%) but also a significantly improved computation time.

Structural basis for specificity and promiscuity in a carrier protein/enzyme system from the sulfur cycle.

The bacterial Sox (sulfur oxidation) pathway is an important route for the oxidation of inorganic sulfur compounds. Intermediates in the Sox pathway are covalently attached to the heterodimeric carrier protein SoxYZ through conjugation to a cysteine on a protein swinging arm. We have investigated how the carrier protein shuttles intermediates between the enzymes of the Sox pathway using the interaction between SoxYZ and the enzyme SoxB as our model. The carrier protein and enzyme interact only weakly, but we have trapped their complex by using a "suicide enzyme" strategy in which an engineered cysteine in the SoxB active site forms a disulfide bond with the incoming carrier arm cysteine. The structure of this trapped complex, together with calorimetric data, identifies sites of protein-protein interaction both at the entrance to the enzyme active site tunnel and at a second, distal, site. We find that the enzyme distinguishes between the substrate and product forms of the carrier protein through differences in their interaction kinetics and deduce that this behavior arises from substrate-specific stabilization of a conformational change in the enzyme active site. Our analysis also suggests how the carrier arm-bound substrate group is able to outcompete the adjacent C-terminal carboxylate of the carrier arm for binding to the active site metal ions. We infer that similar principles underlie carrier protein interactions with other enzymes of the Sox pathway.

Structures of CD6 and Its Ligand CD166 Give Insight into Their Interaction.

CD6 is a transmembrane protein with an extracellular region containing three scavenger receptor cysteine rich (SRCR) domains. The membrane proximal domain of CD6 binds the N-terminal immunoglobulin superfamily (IgSF) domain of another cell surface receptor, CD166, which also engages in homophilic interactions. CD6 expression is mainly restricted to T cells, and the interaction between CD6 and CD166 regulates T-cell activation. We have solved the X-ray crystal structures of the three SRCR domains of CD6 and two N-terminal domains of CD166. This first structure of consecutive SRCR domains reveals a nonlinear organization. We characterized the binding sites on CD6 and CD166 and showed that a SNP in CD6 causes glycosylation that hinders the CD6/CD166 interaction. Native mass spectrometry analysis showed that there is competition between the heterophilic and homophilic interactions. These data give insight into how interactions of consecutive SRCR domains are perturbed by SNPs and potential therapeutic reagents.

Expression levels of MHC class I molecules are inversely correlated with promiscuity of peptide binding.

Highly polymorphic major histocompatibility complex (MHC) molecules are at the heart of adaptive immune responses, playing crucial roles in many kinds of disease and in vaccination. We report that breadth of peptide presentation and level of cell surface expression of class I molecules are inversely correlated in both chickens and humans. This relationship correlates with protective responses against infectious pathogens including Marek's disease virus leading to lethal tumours in chickens and human immunodeficiency virus infection progressing to AIDS in humans. We propose that differences in peptide binding repertoire define two groups of MHC class I molecules strategically evolved as generalists and specialists for different modes of pathogen resistance. We suggest that differences in cell surface expression level ensure the development of optimal peripheral T cell responses. The inverse relationship of peptide repertoire and expression is evidently a fundamental property of MHC molecules, with ramifications extending beyond immunology and medicine to evolutionary biology and conservation.

Measurement of dynamic scapular kinematics using an acromion marker cluster to minimize skin movement artifact.

The measurement of dynamic scapular kinematics is complex due to the sliding nature of the scapula beneath the skin surface. The aim of the study was to clearly describe the acromion marker cluster (AMC) method of determining scapular kinematics when using a passive marker motion capture system, with consideration for the sources of error which could affect the validity and reliability of measurements. The AMC method involves placing a cluster of markers over the posterior acromion, and through calibration of anatomical landmarks with respect to the marker cluster it is possible to obtain valid measurements of scapular kinematics. The reliability of the method was examined between two days in a group of 15 healthy individuals (aged 19-38 years, eight males) as they performed arm elevation, to 120°, and lowering in the frontal, scapular and sagittal planes. Results showed that between-day reliability was good for upward scapular rotation (Coefficient of Multiple Correlation; CMC = 0.92) and posterior tilt (CMC = 0.70) but fair for internal rotation (CMC = 0.53) during the arm elevation phase. The waveform error was lower for upward rotation (2.7° to 4.4°) and posterior tilt (1.3° to 2.8°), compared to internal rotation (5.4° to 7.3°). The reliability during the lowering phase was comparable to results observed during the elevation phase. If the protocol outlined in this study is adhered to, the AMC provides a reliable measurement of upward rotation and posterior tilt during the elevation and lowering phases of arm movement.

Mechanism of thiosulfate oxidation in the SoxA family of cysteine-ligated cytochromes.

Thiosulfate dehydrogenase (TsdA) catalyzes the oxidation of two thiosulfate molecules to form tetrathionate and is predicted to use an unusual cysteine-ligated heme as the catalytic cofactor. We have determined the structure of Allochromatium vinosum TsdA to a resolution of 1.3 Å. This structure confirms the active site heme ligation, identifies a thiosulfate binding site within the active site cavity, and reveals an electron transfer route from the catalytic heme, through a second heme group to the external electron acceptor. We provide multiple lines of evidence that the catalytic reaction proceeds through the intermediate formation of a S-thiosulfonate derivative of the heme cysteine ligand: the cysteine is reactive and is accessible to electrophilic attack; cysteine S-thiosulfonate is formed by the addition of thiosulfate or following the reverse reaction with tetrathionate; the S-thiosulfonate modification is removed through catalysis; and alkylating the cysteine blocks activity. Active site amino acid residues required for catalysis were identified by mutagenesis and are inferred to also play a role in stabilizing the S-thiosulfonate intermediate. The enzyme SoxAX, which catalyzes the first step in the bacterial Sox thiosulfate oxidation pathway, is homologous to TsdA and can be inferred to use a related catalytic mechanism.

Surface texture detection with artificial fingers.

This paper highlights the potential of using prosthetic devices to sense surface textures; an important characteristic of a lower arm that is often neglected. An artificial finger equipped with a piezoelectric sensor, mounted on a fingertip, has been designed to detect surface textures of different dimensions. Signal frequencies generated during the exploratory movement of the artificial finger reliably correlate to all the widths of grooves and ridges of the surface textures under investigation. This capability provides a positive outlook in recreating a touch sensation that has been previously lost from natural fingers and palms.

Objective classification of scapular kinematics in participants with movement faults of the scapula on clinical assessment.

The aim of this study was to assess the potential of employing a classification tool to objectively classify participants with clinically assessed movement faults (MFs) of the scapula. Six participants with a history of shoulder pain with MFs of the scapula and 12 healthy participants with no movement faults (NMFs) performed a flexion movement control test of the scapula, while scapular kinematic data were collected. Principal component scores and discrete kinematic variables were used as input into a classifier. Five out of the six participants with a history of pain were successfully classified as having scapular MFs with an accuracy of 72%. Variables related to the upward rotation of the scapula had the most influence on the classification. The results of the study demonstrate the potential of adopting a multivariate approach in objective classification of participants with altered scapular kinematics in pathological groups.