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A feline model of spontaneously occurring autoimmune limbic encephalitis.
Autoimmune encephalitis (AE) is an important cause of encephalitis in humans and occurs at a similar rate to infectious encephalitis. It is frequently associated with antibodies against the extracellular domain of neuronal proteins. Among human AE, that with antibodies against leucine-rich glioma-inactivated 1 (LGI1) is one of the most prevalent forms, and was recently described in cats with limbic encephalitis (LE). In this study, we describe a large cohort (n = 32) of cats with AE, tested positive for voltage gated potassium channel (VGKC)-antibodies, of which 26 (81%) harboured LGI1-antibodies. We delineate their clinical and paraclinical features as well as long-term outcomes up to 5 years. Similar to human cases, most cats with LGI1-antibodies had a history of focal seizures (83%), clustering in the majority (88%), with interictal behavioural changes (73%). Among feline AE patients, there was no seizure type or other clinical characteristic that could distinguish LGI1-antibody positive from negative cats, unlike the pathognomic faciobrachial dystonic seizures seen in humans. Although six cats were euthanased in the first year for epilepsy-associated reasons, those attaining at least 1-year survival had good seizure control and quality of life with appropriate veterinary care and medication. Acute-phase immunotherapy (prednisolone) was given to the most severely unwell cases and its effect is retrospectively evaluated in 10 cats. Our data show LGI1-antibodies are an important cause of feline encephalitis, sharing many features with human AE. Further research should examine optimal therapeutic management strategies and the cause of LE in seronegative cats, building on paradigms established in the counterpart human disease.
Screening for pathogenic neuronal autoantibodies in serum and CSF of patients with first-episode psychosis.
Patients with autoimmune encephalitides, especially those with antibodies to the N-methyl-D-aspartate receptor (NMDAR), often present with prominent psychosis and respond well to immunotherapies. Although most patients progress to develop various neurological symptoms, it has been hypothesised that a subgroup of patients with first-episode psychosis (FEP) suffer from a forme fruste of autoimmune encephalitis. Without accurate identification, this immunotherapy-responsive subgroup may be denied disease-modifying treatments. Thirty studies addressing aspects of this hypothesis were identified in a systematic review. Amongst other shortcomings, 15/30 reported no control group and only 6/30 determined cerebrospinal fluid (CSF) autoantibodies. To ourselves address these-and other-limitations, we investigated a prospectively ascertained clinically well-characterised cohort of 71 FEP patients without traditional neurological features, and 48 healthy controls. Serum and CSF were tested for autoantibodies against seven neuronal surface autoantigens using live cell-based assays. These identified 3/71 (4%) patient sera with weak binding to either contactin-associated protein-like 2, the NMDAR or glycine receptor versus no binding from 48 control samples (p = 0.28, Fisher's test). The three seropositive individuals showed no CSF autoantibodies and no differences from the autoantibody-negative patients in their clinical phenotypes, or across multiple parameters of peripheral and central inflammation. All individuals were negative for CSF NMDAR antibodies. In conclusion, formes frustes of autoimmune encephalitis are not prevalent among FEP patients admitted to psychiatric care. Our findings do not support screening for neuronal surface autoantibodies in unselected psychotic patients.
Progressive encephalomyelitis with rigidity: A Taiwanese case and review of literature.
INTRODUCTION: Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare disorder. However, the outcome is still variable with different serological and tumor associations, and the elements to good response with less relapse is yet to be elucidated. METHOD: We present a case and obtain a literature review of patients with PERM and make comparisons based on different serological groups. We also analyze patients with idiopathic PERM that had detailed medical records. RESULTS: 81 patients were collected and analyzed. The largest group were glycine receptor-antibody (GlyR-Ab)-positive (70%), and the seropositive-GlyR-Ab-negative group had better response to immunotherapy. Malignancy can occur up to 2 years from the presentation of PERM. Among the 18 cases with detailed records, the patients who had good outcome initiate immunotherapy within 2 months from presentation. 9 of the 12 patients who experienced no relapse had non-steroid immunotherapy. The maximal interval time of relapse was 24 months. CONCLUSION: We recommend tumor surveillance up to 2 years in patients with PERM and early administration of immunotherapies and maintain with non-steroid immunotherapy with or without oral corticosteroid for a minimum of 2 years to reduce the risk of relapse in GlyR-Ab-positive patients.
Ethics of Identifying Individuals Involved in HIV Transmission Events by Phylogenetics in Molecular Surveillance.
Molecular HIV surveillance, involving the collection and analysis of HIV genome sequences, has become an integral part of public health programmes in high-income countries. By employing phylogenetic analysis, molecular HIV surveillance can identify individuals and their positions within networks of HIV transmission. While the primary aim of molecular surveillance is to yield public health benefits, such as linking people to care and reducing transmission, it also poses risks and potential infringements on individual privacy and liberty. This paper examines the ethical implications of using phylogenetics to identify individuals involved in multiple transmission events in high-income countries. Although public health responses tailored to such individuals can significantly reduce further transmission, these individuals often face multiple intersecting vulnerabilities and bear the greatest risks associated with molecular surveillance. We analyze the risks related to privacy, stigma, mistrust, criminalization, and liberty infringements, alongside the benefits of preventing further transmission and increasing healthcare engagement for people living with HIV. We conclude by outlining plausible and ethically acceptable policy options for molecular surveillance practice.
Clinical value of cell-based assays in the characterisation of seronegative myasthenia gravis.
OBJECTIVE: Patients with myasthenia gravis without acetylcholine receptor (AChR) or muscle-specific kinase (MuSK) antibodies detected by radioimmunoprecipitation assays (RIAs) are classified as seronegative myasthenia gravis (SNMG). Live cell-based assays (l-CBAs) can detect additional antibodies to clustered AChR, MuSK and low-density lipoprotein receptor-related protein 4 (LRP4), but positivity rates are variable and both clinical relevance and utility of CBA platforms remain unclear. METHODS: Sera from 82 patients with SNMG were tested by l-CBAs. Human embryonic kidney cells were transfected to individually express clustered AChR, MuSK or LRP4; or transfected to jointly express both clustered adult AChR and MuSK. Sera from 30 and 20 patients positive by RIA for AChR or MuSK antibodies were used as comparators. RESULTS: 53 of 82 (72%) patients with SNMG had generalised and 29 (28%) had ocular disease. The clustered AChR CBA detected antibodies in 16 of 82 patients (19.5%; including 4 patients with solely fetal AChR antibodies), while 7 of 82 (8.5%) patients had MuSK antibodies. A novel exploratory combined adult AChR-MuSK l-CBA efficiently detected all these antibodies in a subset of the SNMG cohort. No LRP4 antibodies were identified. Overall, patients with SNMG with clustered AChR antibodies, CBA-positive MuSK-MG or triple seronegative were younger, had less severe disease than patients with RIA-positive MG and had a better clinical outcome when immunotherapy was started soon after disease onset, although the time interval from onset to immunotherapy was not different when compared with patients with RIA-positive MG. CONCLUSION: Around one-third of patients with SNMG had AChR or MuSK antibodies by l-CBAs, which were efficiently detected with a combined l-CBA. The results in this large and unselected cohort of patients with MG demonstrate the diagnostic usefulness of performing CBAs and the importance of making these tests more widely available.
Rationale and Ethical Assessment of an Oropharyngeal Gonorrhea Controlled Human Infection Model.
Infection with Neisseria gonorrhoeae, the causative agent of gonorrhea, causes significant morbidity worldwide and can have long-term impacts on reproductive health. The greatest global burden of gonorrhea occurs in low- and middle-income settings. Global public health significance is increasing due to rising antimicrobial resistance, which threatens future gonorrhea management. The oropharynx is an important asymptomatic reservoir for gonorrhea transmission and a high-risk site for development of antimicrobial resistance and treatment failure. Controlled human infection model (CHIM) studies using N gonorrhoeae may provide a means to accelerate the development of urgently needed therapeutics, vaccines, and other biomedical prevention strategies. A gonorrhea urethritis CHIM has been used since the 1980s with no reported serious adverse events. Here, we describe the rationale for an oropharyngeal gonorrhea CHIM, including analysis of potential ethical issues that should inform the development of this novel study design.
Trends in malaria prevalence among school-age children in Mainland Tanzania, 2015-2023: A multilevel survey analysis.
In high-transmission areas, school-aged children have higher malaria prevalence and contribute significantly to the transmission reservoir. Malaria infections can be asymptomatic or present with symptoms which may contribute to anaemia, severe illness and fatal malaria. This analysis provides trends of malaria prevalence and associated risk factors among school-aged children in mainland Tanzania. Data for this analysis were obtained from nationwide school malaria surveillance conducted every other year from 2015 to 2023. A total of 307,999 school children aged 5-16 years old from 850 public primary schools were tested for malaria infection using rapid diagnostic tests, assessed for malaria control intervention coverage and other malaria-related parameters. A multilevel mixed-effects logistic regression model was used to assess associated risk factors. Overall malaria prevalence was 21.6% (95%CI: 21.3-22.0) in 2015 which progressively decreased to 11.8% (95%CI: 11.5-12.0 p <0.001) in 2021 with no significant change in the overall malaria risk between 2021 and 2023 (AOR 1.32, CI: 0.92-1.81, p=0.08). School children aged between 9-12 years and 13-16 years had 20% higher risk of malaria (95% CI: 1.15-1.25) and 21% higher risk of malaria (95% CI: 1.16-1.27), respectively, compared to those aged between 5-8 years. Geographically, children from the Lake zone had the highest odds of prevalence (AOR: 18.75; 95% CI: 12.91-27.23) compared to the Central zone, and sleeping under an insecticide-treated net demonstrated a protective effect (AOR=0.68, 95%CI: 0.64-0.72, p < 0.001). There was a significant decline in the prevalence of malaria infection across the study period. We presented a countrywide active surveillance data, collected over time and in different settings which are unique and seldom presented. We believe various stakeholders will use our findings and join force to combat malaria not just in Tanzania but, in all malaria endemic countries.
Ultrahigh frequencies of peripherally matured LGI1- and CASPR2-reactive B cells characterize the cerebrospinal fluid in autoimmune encephalitis.
Intrathecal synthesis of central nervous system (CNS)-reactive autoantibodies is observed across patients with autoimmune encephalitis (AE), who show multiple residual neurobehavioral deficits and relapses despite immunotherapies. We leveraged two common forms of AE, mediated by leucine-rich glioma inactivated-1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies, as human models to comprehensively reconstruct and profile cerebrospinal fluid (CSF) B cell receptor (BCR) characteristics. We hypothesized that the resultant observations would both inform the observed therapeutic gap and determine the contribution of intrathecal maturation to pathogenic B cell lineages. From the CSF of three patients, 381 cognate-paired IgG BCRs were isolated by cell sorting and scRNA-seq, and 166 expressed as monoclonal antibodies (mAbs). Sixty-two percent of mAbs from singleton BCRs reacted with either LGI1 or CASPR2 and, strikingly, this rose to 100% of cells in clonal groups with ≥4 members. These autoantigen-reactivities were more concentrated within antibody-secreting cells (ASCs) versus B cells (P < 0.0001), and both these cell types were more differentiated than LGI1- and CASPR2-unreactive counterparts. Despite greater differentiation, autoantigen-reactive cells had acquired few mutations intrathecally and showed minimal variation in autoantigen affinities within clonal expansions. Also, limited CSF T cell receptor clonality was observed. In contrast, a comparison of germline-encoded BCRs versus the founder intrathecal clone revealed marked gains in both affinity and mutational distances (P = 0.004 and P < 0.0001, respectively). Taken together, in patients with LGI1 and CASPR2 antibody encephalitis, our results identify CSF as a compartment with a remarkably high frequency of clonally expanded autoantigen-reactive ASCs whose BCR maturity appears dominantly acquired outside the CNS.
Use of integrated services in antenatal care: A case study of Mabvuku Polyclinic, Zimbabwe.
BACKGROUND: The integration of diagnostic services presents a critical opportunity to improve health outcomes in low- and middle-income countries (LMICs), potentially averting up to 1 million premature deaths annually. Antenatal care provides a critical platform for diagnosing multiple diseases in an integrated manner. AIM: This study explored the experiences of healthcare providers and pregnant women using integrated diagnostic services at a primary care facility in Zimbabwe. SETTING: A qualitative case study was conducted at Mabvuku Polyclinic in Harare, Zimbabwe. METHODS: Using purposive sampling, 14 healthcare workers and 22 pregnant women participated in interviews. Observations and semi-structured interviews were recorded, transcribed and analysed using NVivo software. Thematic analysis was applied to identify key themes related to access, patient-provider interactions and systemic barriers. RESULTS: According to the interviewees' reports, challenges such as limited resources, medical equipment and staff hinder efforts to integrate diagnostic services. The women strongly preferred integrated diagnosis, even if it meant enduring long waiting times, and valued the convenience of receiving all necessary services in a single visit. The study highlighted the hidden socio-economic barriers to 'free' healthcare and underscored the importance of addressing systemic inefficiencies. CONCLUSION: The insights gained from this study are transferable and contribute to the understanding of integrated diagnostic services in maternal healthcare contexts.Contribution: They offer practical recommendations for improving service delivery and health outcomes in similar settings.
Exploring the levels of variation, inequality and use of physical activity intervention referrals in England primary care from 2017-2020: a retrospective cohort study.
OBJECTIVES: In this study, we explore the use of physical activity intervention referrals in primary care in England and compare their use with the rate of cardiovascular disease (CVD) risk factors in England from 2017 to 2020. We also explore variation and inequalities in referrals to these interventions in England across the study period. DESIGN: Retrospective cohort study. SETTING: England primary care via the Royal College of General Practitioners Research Surveillance Centre. PARTICIPANTS: The Royal College of General Practitioners Research Surveillance Centre, a sentinel network across England covering a population of over 15 000 000 registered patients, was used for data analyses covering the 2017-2020 financial years and including patients with long-term conditions indicating CVD risk factors. OUTCOME MEASURES: An existing ontology of primary care codes was used to capture physical activity interventions and a new ontology was designed to cover long-term conditions indicating CVD risk factors. Single factor analysis of variance, paired samples t-test and two-tailed, one proportion z-tests were used to determine the significance of our findings. RESULTS: We observed statistically significant variation in physical activity intervention referrals for people with CVD risk factors from different ethnic groups and age groups across different regions of England as well as a marked decrease during the COVID-19 pandemic. Interestingly, a significant difference was not seen for different socioeconomic groups or sexes. Across all attributes and time periods (with the exception of the 18-39 group, 2017-2019), we observed a statistically significant underuse of physical activity intervention referrals. CONCLUSIONS: Our findings identified statistically significant variation and underuse of physical activity referrals in primary care in England for individuals at risk of CVD for different population subgroups, especially different ethnicities and age groups, across different regions of England and across time, with the COVID-19 pandemic exerting a significant negative impact on referral rates.
Assessing Sustainable and Healthy Diets in Large-Scale Surveys: Validity and Applicability of a Dietary Index Based on a Brief Food Group Propensity Questionnaire Representing the EAT-Lancet Planetary Health Diet
Background: Ensuring healthy diets within planetary boundaries is essential. However, current instruments measuring adherence to the EAT-Lancet planetary health diet are unsuitable for large-scale surveys. Simplified tools assessing consumption frequency can improve response rates, lower costs, and facilitate administration. Objectives: This study aimed to develop a practical and concise index for evaluating relative adherence to the EAT-Lancet diet across large-scale multicountry surveys. Methods: First, the EAT-Lancet Consumption Frequency Index (ELFI) was developed using a brief food propensity questionnaire of 14 food groups representing the planetary health diet from the Food systems that support transitions to hEalthy And Sustainable dieTs survey, which encompassed 27 European countries (n = 27,417). Subsequently, ELFI was further validated using 24-h dietary recalls from the Third French Individual and National Food Consumption Survey (n = 1645), correlating it with the valid EAT-Lancet Index (ELI), which evaluates absolute adherence, as well as with food group consumption, measures of nutritional health (nutrient adequacy and diet quality), and environmental impact. Analyses included assessment of reliability, structural validity, concurrent validity, and nomological validity. Results: ELFI showed strong reliability (α > 0.80) and factor analysis revealed a 2-factor solution: “foods to encourage” and “foods to balance and to limit.” Confirmatory factor analysis demonstrated that ELFI is structurally valid. Concurrent validity was confirmed as it was associated with sex, age, education, income, household size, physical activity, and smoking habit (P < 0.05). ELFI correlated with ELI (0.44, P < 0.0001) and food group consumptions. Regarding nomological validity, the ELFI subscores for “foods to encourage” and “foods to balance and to limit” were associated with better nutritional health (β = 0.62 and 0.23, respectively; P < 0.0001) and a lower environmental impact (β = –0.16 and –0.36, respectively; P < 0.0001). Conclusions: ELFI approach represents a valuable and easy-to-implement index for evaluating relative adherence to sustainable and healthy diets in large-scale multicountry studies.
Implementing community-based interventions for the management of chronic conditions in low- and middle-income countries: A scoping review of qualitative evidence.
The rising prevalence of chronic diseases in low- and middle-income countries (LMICs) poses significant challenges to already overburdened health systems. Community-based interventions are recognised as effective strategies for managing these conditions. However, implementing such interventions faces barriers that can hinder their effectiveness. This scoping review aims to assess qualitative studies examining barriers and facilitators to implementing community-based interventions for chronic disease management in LMICs. We searched six databases for studies published between 2013-2024. Eligible studies were those with a qualitative design that explored implementation challenges and facilitators of community-based interventions. Data were thematically analysed and interpreted using the Socio-Ecological Model (SEM) to capture multi-level influences on implementation. Eighteen studies were included, covering interventions in 13 LMICs. We identified four levels of influencing the implementation of chronic condition management interventions: individual (service users and providers), community, health system/policy, and interpersonal. Barriers at the individual level included privacy concerns, misconceptions about CHW roles, and a preference for traditional medicine. Facilitators included strong CHW motivation, often driven by personal experiences with the conditions they managed. Community-level support, particularly from local leaders and sensitization events, enhanced intervention acceptance. At the health system level, training quality and role recognition of CHWs were critical, while barriers included excessive workload and insufficient infrastructure. Interpersonal relationships, especially gender dynamics and attitudes of facility-based workers towards CHWs, also influenced implementation outcomes. The quality of qualitative evidence varied, with many studies lacking clear objectives and data collection or analysis frameworks. Effective implementation of community-based interventions for chronic disease management in LMICs requires addressing both systemic and interpersonal barriers. Future interventions should emphasise structured community engagement, comprehensive training, and better integration with healthcare systems. Additionally, improving the methodological rigor of qualitative research is essential for gaining deeper insights into the complex factors that influence the success and sustainability of these interventions.
Community-acquired pneumonia identification from electronic health records in the absence of a gold standard: A Bayesian latent class analysis.
Community-acquired pneumonia (CAP) is common and a significant cause of mortality. However, CAP surveillance commonly relies on diagnostic codes from electronic health records (EHRs), with imperfect accuracy. We used Bayesian latent class models with multiple imputation to assess the accuracy of CAP diagnostic codes in the absence of a gold standard and to explore the contribution of various EHR data sources in improving CAP identification. Using 491,681 hospital admissions in Oxfordshire, UK, from 2016 to 2023, we investigated four EHR-based algorithms for CAP detection based on 1) primary diagnostic codes, 2) clinician-documented indications for antibiotic prescriptions, 3) radiology free-text reports, and 4) vital signs and blood tests. The estimated prevalence of CAP as the reason for emergency hospital admission was 13.6% (95% credible interval 13.3-14.0%). Primary diagnostic codes had low sensitivity but a high specificity (best fitting model, 0.275 and 0.997 respectively), as did vital signs with blood tests (0.348 and 0.963). Antibiotic indication text had a higher sensitivity (0.590) but a lower specificity (0.982), with radiology reports intermediate (0.485 and 0.960). Defining CAP as present when detected by any algorithm produced sensitivity and specificity of 0.873 and 0.905 respectively. Results remained consistent using alternative priors and in sensitivity analyses. Relying solely on diagnostic codes for CAP surveillance leads to substantial under-detection; combining EHR data across multiple algorithms enhances identification accuracy. Bayesian latent class analysis-based approaches could improve CAP surveillance and epidemiological estimates by integrating multiple EHR sources, even without a gold standard for CAP diagnosis.
Is age associated with different vital signs in adults presenting to hospital with bacterial infection? A systematic review and meta-analysis.
BACKGROUND: It has long been suspected that the vital sign abnormalities that accompany bacterial infection are subtle or absent in older adults. This review summarises the evidence for whether older adults present with different vital sign abnormalities to younger adults when hospitalised with bacterial infection. METHODS: MEDLINE, EMBASE and CINAHL EBSCO were searched from inception to 19 December 2024 for English-language research articles of patients hospitalised with bacterial infection reporting age and admission vital signs. We used meta-regression to assess how vital signs vary with age. Where studies reported vital signs in multiple age groups, we undertook a meta-analysis in younger (<65) and older patients (≥65). Evidence quality was assessed using an adapted Quality Assessment of Diagnostic Accuracy Studies-2 tool. RESULTS: Our search yielded 14 487 studies; 132 were included after screening. Older adults were less likely to be tachycardic (RR 0.82, 0.69 to 0.97, I2 = 86.5%) with a mean difference in heart rate of 5 bpm (-7 to -3 bpm, I2 = 88.3%). Older adults were less likely to be febrile (RR 0.89, 0.83 to 0.95, I2 = 85.9%) with a mean difference in temperature of 0.14°C (-0.26 to -0.02°C, I2 = 94.6%). Most (129/132) studies were at high risk of bias. CONCLUSIONS: Whilst differences in absolute values were small, there was consistency in the finding that older adults were less likely than younger adults to be tachycardic or febrile. As vital signs at presentation may prompt suspicion of infection, influencing investigations and treatment, special consideration for the possibility of infection in older patients with normal vital signs may be warranted.
Bivalent prefusion F vaccination in pregnancy and respiratory syncytial virus hospitalisation in infants in the UK: results of a multicentre, test-negative, case-control study.
BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections (ALRI) in infants younger than 6 months globally. A maternal bivalent RSV prefusion F (RSVpreF) vaccine was introduced to the UK in late summer in 2024 (August 12 in Scotland and September 1 in England), with all pregnant women at 28 weeks or more of gestation eligible for vaccination. We aimed to understand RSVpreF vaccine effectiveness in a real-world setting. METHODS: We conducted a multicentre, test-negative, case-control study to analyse the vaccine effectiveness of maternal RSVpreF vaccination against the primary outcome of hospitalisation (ie, admission to hospital) for RSV-associated ALRI in infants. Patient and public involvement from a group of parents informed the study protocol design. Included patients were infants with ALRI born after Aug 12, 2024 (Scotland), and Sept 1, 2024 (England), and therefore had mothers eligible for maternal vaccination, who were admitted to 30 hospital sites across the UK from Sept 30, 2024, to Jan 20, 2025, and tested for RSV. Infants were followed up until hospital discharge or death as an inpatient. Primary vaccine effectiveness of maternal RSVpreF vaccination against RSV-associated hospitalisation was calculated with the use of a conditional logistic regression adjusted by site, calendar month of hospital attendance for the infant, age, preterm birth, and sex. FINDINGS: We included 537 mother-infant pairs, in whom there were 391 RSV-positive infant cases (median age 1·63 months [IQR 0·94-2·26]) and 146 RSV-negative infant controls (1·41 months [0·77-2·03]). Of 537 recruited infants, 297 (55%) were male and 240 (45%) were female. Ethnicity data were available for 533 mothers, of whom 434 (81%) self-identified as White. The mothers of 73 (19%) RSV-positive cases and 60 (41%) RSV-negative controls had received RSVpreF vaccine before delivery. The adjusted effectiveness of maternal RSVpreF vaccination for preventing infant hospitalisation was 58% (95% CI 28-75) for infants whose mothers were vaccinated at any time before delivery and 72% (48-85) for infants whose mothers were vaccinated more than 14 days before delivery (39 [11%] of 357 RSV-positive cases vs 43 [33%] of 129 RSV-negative controls). INTERPRETATION: In the real-world setting of the first season of vaccine implementation in England and Scotland, maternal RSVpreF vaccination was effective and equivalent to trial settings in reducing the risk of hospitalisation in infants with RSV-associated ALRI. FUNDING: National Institute for Health and Care Research, The Wellcome Trust, and Imperial College London.