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High epilepsy prevalence and excess mortality in onchocerciasis-endemic counties of South Sudan: A call for integrated interventions.
BACKGROUND: Epilepsy is a major health concern in onchocerciasis-endemic regions with intense transmission, where the infection is associated with a high epilepsy burden. This study investigated epilepsy prevalence and mortality in five onchocerciasis-endemic counties of South Sudan, and the association between onchocerciasis transmission and epilepsy, including probable nodding syndrome (pNS). METHODOLOGY: House-to-house cross-sectional surveys (2021-2024) identified persons with suspected epilepsy (sPWE) and retrospectively documented deaths among sPWE and individuals without epilepsy (IWE). Epilepsy diagnoses, including pNS, were confirmed by trained clinicians. Ongoing transmission was assessed using anti-Ov16 seroprevalence in children aged 3‒9 years. Age- and sex-standardised epilepsy, pNS and anti-Ov16 prevalence were calculated, along with age- and sex-standardised mortality rates and standardised mortality ratios (SMRs) with 95% confidence intervals (95%CIs), using IWE as the reference population. Weighted arcsin-transformed linear regression was used to explore the association between epilepsy and anti-Ov16 prevalence. PRINCIPAL FINDINGS: Among 34,019 individuals screened, 166 deaths occurred in 3,101 person-years for sPWE versus 466 deaths in 63,420 person-years for IWE. Epilepsy prevalence was 4.1% (range: 2.3-7.1%), and pNS prevalence was 1.5% (range: 0.6-2.2%). Anti-Ov16 seroprevalence among children was 23.3% (range: 1.4-44.1%). Each 1.0 percentage point increase in standardised anti-Ov16 seroprevalence was statistically significantly associated with an average rise of 0.10 percentage points in standardised epilepsy prevalence and 0.04 percentage points in standardised pNS prevalence. Median age at death was lower for sPWE (20 years) than IWE (38 years; Mann-Whitney U-test p-value
Sex and age predict habitat selection in the world's most geographically extensive lion population.
Conservation of large carnivore populations requires effective management strategies that promote landscape-scale protection and genetic connectivity. Pivotal to the success of these strategies is sufficient evidence, including quantifying the processes that govern species distribution. We used telemetry data from 63 lions from the Kavango-Zambezi Transfrontier Conservation Area (KAZA TFCA) in southern Africa to analyze inter-demographic differences in habitat relationships using a mixed-effects resource selection analysis approach. In this semi-arid landscape, some of the most important drivers of habitat selection are surface water and precipitation, which in turn regulate prey abundance. Predicted relative probability of habitat selection was highest near water irrespective of age and sex; however, the effect of precipitation varied depending on the demographic class. Adult lions and subadult females preferred habitat with above average rainfall; however, the opposite was true for subadult males which showed a strong aversion to precipitation. Across all four demographic classes, relative probability of habitat selection was generally positively associated with higher levels of prey abundance with the exception of gemsbok which was negatively correlated with adult female, subadult male, and subadult female habitat use. The predicted distributions for all four demographic classes were widespread across multiple different land-use types, highlighting the need to extend the traditional concept of formally protected areas to include multi-use landscapes and support large-scale transboundary conservation initiatives.
Social resource as a critical and overlooked factor for patient safety in low-resource settings.
Clinicians, NGOs, funders and academics (among others) in global health are accustomed to discussion of the "low-resource setting". Commonly, the resources implicit in this term are physical (equipment, drugs) and infrastructural (electricity, water and sanitation) in nature. Human resources are well recognised as scarce in this context too, and the focus in most "workforce" research is on the number, distribution and/or training of healthcare workers. In this article, we make the case for closer examination of "social resource" as necessary to patient safety and distinct from simple enumeration of available/trained personnel. We use the clinical specialty of anaesthesia as a case study, identifying the different ways in which social resource is necessary to enable safe practice for anaesthesia providers, and the potential challenges to accessing social resource relevant in the low- and middle-income context. Finally, we suggest ways in which social resource for anaesthesia professionals in LMICs might be meaningfully investigated, with a view to improving its priority and access for safe anaesthesia care worldwide.
Scavenger receptor CD163 multimerises to allow uptake of diverse ligands.
CD163 is an archetypal scavenger receptor and mediates detoxification of free haemoglobin. Release of haemoglobin from lysed erythrocytes causes oxidative tissue and organ damage. Detoxification involves haemoglobin binding to the abundant serum protein haptoglobin, followed by CD163-mediated uptake of stoichiometrically diverse haptoglobin-haemoglobin complexes into macrophages for degradation. We show that CD163 adopts dimeric and trimeric assemblies due to calcium-mediated interactions within a membrane-associated base. Arms protrude from this base and create a ligand-binding site. Flexibility within the base, coupled with multiple small ligand-binding surfaces on each arm, allow the receptor to mould around its ligands, resulting in promiscuous uptake of ligands with different structures and stoichiometries. Monomeric CD163 lacks this ability to internalise lower-avidity ligands. Arms from adjacent protomers can also self-associate, blocking ligand-binding surfaces in an autoinhibited state. Therefore, through calcium-dependent multimer formation and flexible ligand binding, CD163 scavenges ligands with different structures and avidities, mediating haemoglobin detoxification.
Incidence and Outcomes of Intraductal Oncocytic Papillary Neoplasm-Derived Pancreatic Cancer Compared with Tubular and Colloid Intraductal Papillary Mucinous Neoplasm-Derived Pancreatic Cancer: An International Multicenter Retrospective Study.
BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic cancer was previously categorized into tubular, colloid, and oncocytic subtypes. Intraductal oncocytic papillary neoplasms (IOPN) has long been associated with superior prognosis/indolent behavior, however, there is discordant emerging evidence. This study aimed to investigate this conflicting literature. METHODS: Patients with resected IOPN-derived and IPMN-derived pancreatic cancer were identified from six international centers. Log-rank tests compared time to (TtR) and survival after (SAR) recurrence and five-year overall survival (OS). A multivariable mixed model was used to determine hazard ratios (HR) with confidence intervals (95%CI) for five-year survival. RESULTS: Of 879 patients, 20 (2%) had IOPN-derived pancreatic cancer. Most patients had T1 (55%) or N0 (70%) disease. IOPN and colloid IPMN-derived pancreatic cancers had similar recurrence rates (25% vs. 24%), while recurrence was more common in tubular IPMN-derived pancreatic cancer (42%, p
Development and evaluation of prompts for a large language model to screen titles and abstracts in a living systematic review.
BACKGROUND: Living systematic reviews (LSRs) maintain an updated summary of evidence by incorporating newly published research. While they improve review currency, repeated screening and selection of new references make them labourious and difficult to maintain. Large language models (LLMs) show promise in assisting with screening and data extraction, but more work is needed to achieve the high accuracy required for evidence that informs clinical and policy decisions. OBJECTIVE: The study evaluated the effectiveness of an LLM (GPT-4o) in title and abstract screening compared with human reviewers. METHODS: Human decisions from an LSR on prodopaminergic interventions for anhedonia served as the reference standard. The baseline search results were divided into a development and a test set. Prompts guiding the LLM's eligibility assessments were refined using the development set and evaluated on the test set and two subsequent LSR updates. Consistency of the LLM outputs was also assessed. RESULTS: Prompt development required 1045 records. When applied to the remaining baseline 11 939 records and two updates, the refined prompts achieved 100% sensitivity for studies ultimately included in the review after full-text screening, though sensitivity for records included by humans at the title and abstract stage varied (58-100%) across updates. Simulated workload reductions of 65-85% were observed. Prompt decisions showed high consistency, with minimal false exclusions, satisfying established screening performance benchmarks for systematic reviews. CONCLUSIONS: Refined GPT-4o prompts demonstrated high sensitivity and moderate specificity while reducing human workload. This approach shows potential for integrating LLMs into systematic review workflows to enhance efficiency.
Novel NIBS in psychiatry: Unveiling TUS and TI for research and treatment.
Mental disorders pose a significant global burden and constitute a major cause of disability worldwide. Despite strides in treatment, a substantial number of patients do not respond adequately, underscoring the urgency for innovative approaches. Traditional non-invasive brain stimulation techniques show promise, yet grapple with challenges regarding efficacy and specificity. Variations in mechanistic understanding and reliability among non-invasive brain stimulation methods are common, with limited spatial precision and physical constraints hindering the ability to target subcortical areas often implicated in the disease aetiology. Novel techniques such as transcranial ultrasonic stimulation and temporal interference stimulation have gained notable momentum in recent years, possibly addressing these shortcomings. Transcranial ultrasonic stimulation (TUS) offers exceptional spatial precision and deeper penetration compared with conventional electrical and magnetic stimulation techniques. Studies targeting a diverse array of brain regions have shown its potential to affect neuronal excitability, functional connectivity and symptoms of psychiatric disorders such as major depressive disorder. Nevertheless, challenges such as target planning and addressing acoustic interactions with the skull must be tackled for its widespread adoption in research and potentially clinical settings. Similar to transcranial ultrasonic stimulation, temporal interference (TI) stimulation offers the potential to target deeper subcortical areas compared with traditional non-invasive brain stimulation, albeit requiring a comparatively higher current for equivalent neural effects. Promising yet still sparse research highlights TI's potential to selectively modulate neuronal activity, showing potential for its utility in psychiatry. Overall, recent strides in non-invasive brain stimulation methods like transcranial ultrasonic stimulation and temporal interference stimulation not only open new research avenues but also hold potential as effective treatments in psychiatry. However, realising their full potential necessitates addressing practical challenges and optimising their application effectively.
The cognitive neuroscience of ketamine in major depression.
Ketamine's potential as a rapid-acting antidepressant was first identified in 2000, despite its long-standing use as an anesthetic agent. Clinically, ketamine alleviates depressive symptoms, including the difficult to treat symptom of anhedonia, within hours, with the effects of a single dose lasting for days. Since then, research has focused on uncovering the mechanisms underlying its rapid antidepressant effects in both humans and animal models. While its molecular and cellular effects have been extensively characterized, its impact on cognitive and neuropsychological mechanisms - potential mediators of its clinical efficacy - remains an area of ongoing investigation. Preclinical studies suggest that ketamine rapidly influences the lateral habenula (involved in punishment processing) and fronto-striatal (reward) systems, reverses negative affective biases in established memories, and promotes long-term stress resilience. Translating these findings to human models is crucial, and emerging evidence suggests that ketamine engages similar mechanisms in healthy volunteer and patient groups. However, its clinical application is constrained by acute side effects and an unknown long-term safety profile. Further research into ketamine's mechanisms of action will be essential to inform the development of novel, safer, and more accessible rapid-acting antidepressants.
Cost-effectiveness of pramipexole in addition to mood stabilisers for patients with treatment-resistant bipolar depression: Economic evaluation of the PAX-BD randomised controlled trial.
BACKGROUND: People with bipolar disorders (BD) frequently experience depressive symptoms that do not respond to available treatment options. The resulting burden for people with BD and society is substantial. This study sought to explore the cost-effectiveness of pramipexole in combination with mood stabilisers for people with treatment-resistant bipolar disorder (TRBD). METHODS: We calculated mean incremental cost ratios (ICER) of pramipexole compared to placebo over 12 and 48 weeks from health and social care (NHS + PSS) and societal perspectives for 36 participants with TRBD. Quality-adjusted life years (QALY) were captured with the EQ-5D-5L as the primary outcome measure. We used capability well-being measures (ICECAP-A, OxCAP-MH) to assess the robustness of the results and multiple imputation and bootstrapping to address missing data and small sample size. RESULTS: We found that pramipexole is more effective and cost-saving from the NHS + PSS perspective. The probability of being cost-effective at £30,000/QALY gained was 70 % (12 weeks) and 90 % (48 weeks). From the societal perspective, pramipexole was more effective but also more expensive with lower probability of cost-effectiveness (33 % at 12 weeks and 47 % at 48 weeks). Uncertainty around the mean ICERs was substantial due to the small sample size. LIMITATIONS: The PAX-BD trial was conducted during the COVID-19 pandemic and terminated early, resulting in a limited generalizability of resource use outside the pandemic context and a small sample size. CONCLUSIONS: Pramipexole is a cost-effective treatment option for TRBD from the NHS + PSS perspective, with statistically significant increases in health-related quality of life and capability well-being over extended periods.
Multi-site feasibility and reproducibility study on UTE 3D phosphorous MRSI using novel rosette trajectory (PETALUTE).
PURPOSE: This study aims (1) to implement a robust acquisition, fully automated reconstruction, and processing pipeline using a novel rosette k-space pattern for UTE 31P 3D MRSI and (2) to evaluate the clinical applicability and reproducibility at different experimental setups. METHODS: A multi-center feasibility/reproducibility study was conducted for the novel UTE 31P 3D MRSI sequence with rosette petal trajectory (PETALUTE) at three institutions with different experimental setups (Siemens Prisma with volume head coil or surface coil, Siemens Biograph mMR with volume head coil). Five healthy subjects at each site were measured with an acquisition delay of 65 μs and a final resolution of 10 × 10 × 10 mm3 in 9 min. The measurement was repeated three times and averaged for the spectral analysis using the LCModel package. The potential for acceleration was assessed using compressed sensing on retrospectively undersampled data. Reproducibility at each site was evaluated using the inter-subject coefficient of variance. RESULTS: This novel acquisition and advanced processing techniques yielded high-quality spectra and enabled the detection of the critical brain metabolites at three different sites with different hardware specifications. In vivo, feasibility with an acceleration factor of 4 in 6.75 min resulted in a mean Cramér-Rao lower bounds below 20% for phosphocreatine (PCr), adenosine triphosphate (ATP), phosphomonoesters (PME), and a mean coefficient of variation for ATP/PCr below 20%. CONCLUSION: We demonstrated that UTE 31P 3D rosette MRSI acquisition, combined with compressed sensing and LCModel analysis, allows clinically feasible, robust, high-resolution 31P MRSI to be acquired at clinical setups.
Lesion level and severity acutely influence metabolomic profiles in spinal cord injury.
Changes in the peripheral metabolome, particularly in the blood, may provide biomarkers for assessing lesion severity and predicting outcomes after spinal cord injury (SCI). Using principal component analysis (PCA) and Orthogonal Partial Least Squares Discriminatory Analysis (OPLS-DA), we sought to discover how SCI severity and location acutely affect the nuclear magnetic resonance-acquired metabolome of the blood, spinal cord, and liver at 6 h post-SCI in mice. Unsupervised PCA of the spinal cord metabolome separated mild (30 kdyne) and severe (70 kdyne) contusion injury groups but did not distinguish between lesion level. However, OPLS-DA could discriminate thoracic level T2 from T9 lesions in both blood plasma (accuracy 86 ± 6%) and liver (accuracy 89 ± 5%) samples. These differences were dependent on alterations in energy metabolites (lactate and glucose), lipoproteins, and lipids. Lactate was the most discriminatory between mild and severe injury at T2, whereas overlapping valine/proline resonances were most discriminatory between injury severities at T9. Plasma lactate correlated with blood-spinal cord barrier breakdown and plasma glucose with microglial density. We propose that peripheral biofluid metabolites can serve as biomarkers of SCI severity and associated pathology at the lesion site; their predictive value is most accurate when the injury level is also considered.