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Ironmaking can have an important role in the circular economy by utilising alternative carbon bearing materials, which are otherwise of low value in use or landfilled. Biomass and plastic wastes have been proposed as alternatives for coke and coal in sintering, blast furnace ironmaking and direct iron ore reduction processes. However, introduction of the alternative carbon sources with higher chlorine contents may influence the formation of some pollutants, most notably, dioxins. This study investigated the effects of carbon bearing materials, i.e., coke, biomass and polyvinyl chloride (PVC), on formation of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and polychlorinated biphenyls (PCBs) during high temperature processing of iron ore. The effect of copper (Cu) as a known dioxin synthesis catalyst, on formation of the dioxins was also investigated. The study found an exponential increasing relationship between the chlorine content in the fuel source and the dioxin emissions. The addition of both biomass and PVC materials contributed to significantly increased dioxin formation, especially for the case of plastics. PCBs had higher concentrations than PCDD/Fs in all cases except when CuCl2 was added due to its catalytic properties to synthesise PCDD/Fs. PCDF concentrations far outweighed the PCDDs, suggesting that de novo reaction mechanism, where carbon particles are oxidised by a transition metal in presence of chlorine, dominated the formation of the dioxins in the process.

Summary: Background: Post-traumatic stress disorder (PTSD) and depression are common after mild traumatic brain injury (mTBI), but their biological drivers are uncertain. We therefore explored whether polygenic risk scores (PRS) derived for PTSD and major depressive disorder (MDD) are associated with the development of cognate TBI-related phenotypes. Methods: Meta-analyses were conducted using data from two multicenter, prospective observational cohort studies of patients with mTBI: the CENTER-TBI study (ClinicalTrials.gov ID NCT02210221) in Europe (December 2014–December 2017) and the TRACK-TBI study in the US (March 2014–July 2018). In both cohorts, the most common causes of injury were road traffic accidents and falls. Primary outcomes, specifically probable PTSD and depression, were defined at 6 months post-injury using scores ≥33 on the PTSD Checklist-5 and ≥15 on the Patient Health Questionnaire-9, respectively. We calculated PTSD-PRS and MDD-PRS for patients aged ≥17 years who had a Glasgow Coma Scale score of 13–15 upon hospital arrival and assessed their association with PTSD and depression following TBI. We also evaluated the transferability of the findings in a cohort of African Americans. Findings: Overall, 11.8% (219/1869) and 6.7% (124/1869) patients were classified as having probable PTSD and depression, respectively. The PTSD-PRS was significantly associated with higher adjusted odds of PTSD in both cohorts, with a pooled odds ratio (OR) of 1.55 [95% confidence interval (CI) 1.30–1.84, p

Chemoprophylactic prevention of veterinary heartworm disease in companion animals, caused by the vector-borne nematode parasite Dirofilaria immitis, is a multi-billion-dollar global market. Experimental use of cats and dogs in preclinical heartworm drug testing is increasing due to evolving drug-resistance to frontline macrocyclic lactones and renewed investment in alternative preventative drug research. We and others recently published data demonstrating proof-of-concept of utilising lymphopenic severe-combined immunodeficient (SCID) or Recombination Activating Gene (RAG)2 deficient mice with additional knockout of the IL-2/7 receptor gamma chain (γc) as alternative preventative drug screening research models of dirofilariasis. Here we summarise the current knowledge of candidate immunodeficient mouse models tested, including a comparison of susceptibility using different background strains of mice, different D. immitis isolates, following use of anti-inflammatory treatments to further suppress residual innate immunity, and efficacies achieved against different reference anthelmintics. We supplement this precis with new data on treatment response to the veterinary anthelmintic, oxfendazole, and initial evaluation of D. immitis susceptibility in CB.17 SCID and C57BL/6 RAG2 -/-γc -/- mice. We conclude that in addition to NSG and NXG mice, RAG2 -/-γc -/- mice on either a BALB/c or C57BL/6 background offer an alternative screening model option, widening access to academic and commercial laboratories wishing to pursue initial rapid in vivo drug screening whilst avoiding potentially unnecessary cat or dog testing.

Chemoprophylactic prevention of veterinary heartworm disease in companion animals, caused by the vector-borne nematode parasite Dirofilaria immitis, is a multi-billion-dollar global market. Experimental use of cats and dogs in preclinical heartworm drug testing is increasing due to evolving drug-resistance to frontline macrocyclic lactones and renewed investment in alternative preventative drug research. We and others recently published data demonstrating proof-of-concept of utilising lymphopenic severe-combined immunodeficient (SCID) or Recombination Activating Gene (RAG)2 deficient mice with additional knockout of the IL-2/7 receptor gamma chain (γc) as alternative preventative drug screening research models of dirofilariasis. Here we summarise the current knowledge of candidate immunodeficient mouse models tested, including a comparison of susceptibility using different background strains of mice, different D. immitis isolates, following use of anti-inflammatory treatments to further suppress residual innate immunity, and efficacies achieved against different reference anthelmintics. We supplement this precis with new data on treatment response to the veterinary anthelmintic, oxfendazole, and initial evaluation of D. immitis susceptibility in CB.17 SCID and C57BL/6 RAG2 -/-γc -/- mice. We conclude that in addition to NSG and NXG mice, RAG2 -/-γc -/- mice on either a BALB/c or C57BL/6 background offer an alternative screening model option, widening access to academic and commercial laboratories wishing to pursue initial rapid in vivo drug screening whilst avoiding potentially unnecessary cat or dog testing.

Abstract Background Research on genetic and environmental influences on speech and/or language difficulties (SaLD) is sparse, with inconsistent heritability estimates. We aimed to estimate the prevalence of parental reported SaLD and the relative contributions of genetic and environmental factors for the phenotype using a Swedish population‐based twin sample. We hypothesized that there would be a stronger genetic than environmental effect on SaLD. Methods Data were collected from The Child and Adolescent Twin Study in Sweden. The study sample included 16,774 twin pairs (16,946 males, 16,602 females), of which 5141 were monozygotic, 5861 dizygotic (DZ), and 5772 opposite‐sex DZ pairs. The language items in the Autism–Tics, Attention‐Deficit Hyperactivity Disorder, and other Comorbidities inventory were used to categorize individuals as having parental‐reported SaLD. A classical twin design was used to estimate the relative contribution of genetic and environmental factors to the liability of SaLD. Results The prevalence of SaLD was 7.85% (95% confidence interval (CI) [7.57%–8.15%]) and 7.27% (95% CI [6.99%–7.55%]) when excluding individuals with autism and intellectual disability (ID). We also found that SaLD were significantly more prevalent in males than females with a ratio of 2:1. The heritability was estimated to be 75% (95% CI [67%–83%]) for SaLD. Shared environment played a significant role with an estimated contribution of 22% (95% CI [14%–30%]). The heritability estimate was reduced to 70% but with overlapping CI when excluding individuals with autism and ID. Conclusions We provide evidence that SaLD is common in the population and under strong genetic influence. Future studies should focus on mapping the genetic architecture of SaLD and related disorders.

Summary: Background: Traumatic brain injury is conventionally categorised as mild, moderate, or severe on the Glasgow Coma Scale (GCS). Recently developed biomarkers can provide more objective and nuanced measures of the extent of brain injury. Methods: Exposure–response relationships were investigated in 2479 patients aged ≥16 enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. Neurofilament protein-light (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) were assayed from serum sampled in the first 24 h; concentrations were divided into quintiles within GCS severity groups. Relationships with the Glasgow Outcome Scale-Extended were examined using modified Poisson regression including age, sex, major extracranial injury, time to sample, and log biomarker concentration as covariates. Findings: Within severity groups there were associations between biomarkers and outcomes after adjustment for covariates: GCS 13–15 and negative CT imaging (relative risks [RRs] from 1.28 to 3.72), GCS 13–15 and positive CT (1.21–2.81), GCS 9–12 (1.16–2.02), GCS 3–8 (1.09–1.94). RRs were associated with clinically important differences in expectations of prognosis. In patients with GCS 3 (RRs 1.51–1.80) percentages of unfavourable outcome were 37–51% in the lowest quintiles of biomarker levels and reached 90–94% in the highest quintiles. Similarly, for GCS 15 (RRs 1.83–3.79), the percentages were 2–4% and 19–28% in the lowest and highest biomarker quintiles, respectively. Interpretation: Conventional TBI severity classification is inadequate and underestimates heterogeneity of brain injury and associated outcomes. The adoption of circulating biomarkers can add to clinical assessment of injury severity. Funding: European Union 7th Framework program (EC grant 602150), Hannelore Kohl Stiftung, One Mind, Integra LifeSciences, Neuro-Trauma Sciences, NIHR Rosetrees Trust.

Chemoprophylactic prevention of veterinary heartworm disease in companion animals, caused by the vector-borne nematode parasite Dirofilaria immitis, is a multi-billion-dollar global market. Experimental use of cats and dogs in preclinical heartworm drug testing is increasing due to evolving drug-resistance to frontline macrocyclic lactones and renewed investment in alternative preventative drug research. We and others recently published data demonstrating proof-of-concept of utilising lymphopenic severe-combined immunodeficient (SCID) or Recombination Activating Gene (RAG)2 deficient mice with additional knockout of the IL-2/7 receptor gamma chain (γc) as alternative preventative drug screening research models of dirofilariasis. Here we summarise the current knowledge of candidate immunodeficient mouse models tested, including a comparison of susceptibility using different background strains of mice, different D. immitis isolates, following use of anti-inflammatory treatments to further suppress residual innate immunity, and efficacies achieved against different reference anthelmintics. We supplement this precis with new data on treatment response to the veterinary anthelmintic, oxfendazole, and initial evaluation of D. immitis susceptibility in CB.17 SCID and C57BL/6 RAG2-/-γc-/- mice. We conclude that in addition to NSG and NXG mice, RAG2-/-γc-/- mice on either a BALB/c or C57BL/6 background offer an alternative screening model option, widening access to academic and commercial laboratories wishing to pursue initial rapid in vivo drug screening whilst avoiding potentially unnecessary cat or dog testing.

Down syndrome regression disorder (DSRD) is a rare condition involving subacute cognitive decline, loss of previously acquired developmental skills, and prominent neuropsychiatric symptoms, particularly catatonia, in people with Down syndrome. It is thought to involve both autoimmune and neuropsychiatric mechanisms. Research, however, is largely restricted to case studies and retrospective case series and is particularly limited in terms of prospective longitudinal follow-up. We report a case study of a person with DSRD who received both immunomodulatory (intravenous immunoglobulin; IVIG) and psychiatric interventions (electroconvulsive therapy, ECT) over two years with regular assessments using caregiver and clinician ratings. This revealed a small, unsustained response to IVIG and a rapid, sustained response once ECT was introduced. The case highlights the importance of multimodal assessment involving multiple medical specialties, the need to trial different therapies due to the condition’s complexity, and the significant barriers that patients and their families face in accessing care.

It can be challenging for practitioners to determine reasonable response actions following an environmental spill because there are risks associated with the recovery process, acute constraints on time, and few case studies available from antecedent events. Here, we evaluate environmental risk using a screening level assessment (SLA) and describe risk management actions during the response phase of a train derailment that released 600 tonnes of fly ash into a headwater creek in Banff National Park, Canada. Trace metal concentrations and physico-chemical parameters from downstream of the derailment site were compared to Canadian environmental quality guidelines and upstream reference values. There was a 1–2.2-fold exceedance of sediment quality guidelines (As, Cd, and Se) as well as a 3.6–17.5-fold exceedance of water quality guidelines (Al, Cd, Fe, and turbidity) downstream of the train derailment. Despite uncertainty about site-specific toxicity when using a SLA, we did require the removal of the settled fly ash from the creek based on the multiple exceedances of guidelines, regulatory context, wilderness setting, and potential contribution to cumulative effects downstream. Case studies that evaluate risk and describe risk management actions help practitioners make consistent and efficient decisions during the response phase of a spill.

Abstract Background There is increasing epidemiological evidence supporting the association between onchocerciasis and seizures, reinforcing the concept of onchocerciasis-associated epilepsy (OAE). The aim of this paper is to provide an update on the new knowledge about OAE and to propose recommendations to the World Health Organization how to address this public health problem. Main text During the 2nd International Workshop on OAE held on 19–21 September, 2023, in Antwerp, Belgium, participants recognised OAE as a substantial yet neglected public health problem, particularly in areas of sub-Saharan Africa where onchocerciasis remains hyperendemic. Evidence from prospective population-based studies suggest that strengthening onchocerciasis elimination efforts leads to a significant reduction of OAE incidence. There is a need to validate an OAE case definition to estimate the burden of disease and identify onchocerciasis-endemic areas requiring intensification of onchocerciasis elimination programmes and integration of epilepsy care. It is expected that raising awareness about OAE will boost the population uptake of ivermectin. The implementation of a community-based epilepsy treatment programme offering free anti-seizure medications (ASMs) has shown high effectiveness in reducing the frequency of seizures and improving the overall quality of life of people with epilepsy. Conclusions To reduce OAE burden, enhanced collaboration between onchocerciasis and mental health programmes at community, national, and international levels is required. Urgent efforts are needed to ensure the uninterrupted provision of free ASMs in onchocerciasis-endemic areas. Furthermore, OAE should be included in the quantification of the onchocerciasis disease burden. Graphical Abstract

Abstract Background Evidence for substance use‐related problems in individuals with mild intellectual disability is sparse and mainly limited to selected psychiatric populations. We evaluated the risk of substance use‐related problems in individuals with mild intellectual disability compared to the general population. Additionally, we have performed secondary sibling comparison analyses to account for familial confounding. Methods We conducted a population‐based cohort study of individuals born in Sweden between 1973 and 2003. A total of 18,307 individuals with mild intellectual disability were compared to 915,350 reference individuals from the general population and 18,996 full siblings of individuals with mild intellectual disability. Information on mild intellectual disability and substance use‐related problems was obtained from several Swedish national and regional school and healthcare registers. Substance use‐related problems were measured via corresponding diagnostic and legal codes and included alcohol use disorder, drug use disorder, alcohol‐related somatic disease, conviction for a substance‐related crime, and substance‐related death. Results Individuals with mild intellectual disability had a higher risk of any substance use‐related problem compared to the general population (HR, 1.81; 95% CI, 1.72–1.91), both in males (HR, 1.76; 95% CI, 1.65–1.89) and females (HR, 1.89; 95% CI, 1.74–2.05). The risks of substance use‐related problems were particularly elevated among individuals with mild intellectual disability and psychiatric comorbidities (HR, 2.21–8.24). The associations were attenuated in the sibling comparison models. Conclusions Individuals with mild intellectual disability, especially those with psychiatric comorbidity, are at an elevated risk of substance use‐related problems. Familial factors shared by full siblings contribute considerably to the association between mild intellectual disability and substance use‐related problems.

Chemoprophylactic prevention of veterinary heartworm disease in companion animals, caused by the vector-borne nematode parasite Dirofilaria immitis, is a multi-billion-dollar global market. Experimental use of cats and dogs in preclinical heartworm drug testing is increasing due to evolving drug-resistance to frontline macrocyclic lactones and renewed investment in alternative preventative drug research. We and others recently published data demonstrating proof-of-concept of utilising lymphopenic severe-combined immunodeficient (SCID) or Recombination Activating Gene (RAG)2 deficient mice with additional knockout of the IL-2/7 receptor gamma chain (γc) as alternative preventative drug screening research models of dirofilariasis. Here we summarise the current knowledge of candidate immunodeficient mouse models tested, including a comparison of susceptibility using different background strains of mice, different D. immitis isolates, following use of anti-inflammatory treatments to further suppress residual innate immunity, and efficacies achieved against different reference anthelmintics. We supplement this precis with new data on treatment response to the veterinary anthelmintic, oxfendazole, and initial evaluation of D. immitis susceptibility in CB.17 SCID and C57BL/6 RAG2-/-γc-/- mice. We conclude that in addition to NSG and NXG mice, RAG2-/-γc-/- mice on either a BALB/c or C57BL/6 background offer an alternative screening model option, widening access to academic and commercial laboratories wishing to pursue initial rapid in vivo drug screening whilst avoiding potentially unnecessary cat or dog testing.

BackgroundIn 2020 the World Health Organization (WHO) declared that Malawi had successfully eliminated lymphatic filariasis (LF) as a public health problem. Understanding clinical case distributions at a national and sub-national level is important, so essential care packages can be provided to individuals living with LF symptoms. This study aimed to develop a national database and map of LF clinical cases across Malawi using geostatistical modelling approaches, programme-identified clinical cases, antigenaemia prevalence and climate information.MethodologyLF clinical cases identified through programme house-to-house surveys across 90 sub-district administrative boundaries (Traditional Authority (TA)) and antigenaemia prevalence from 57 sampled villages in Malawi were used in a two-step geostatistical modelling process to predict LF clinical cases across all TAs of the country. First, we modelled antigenaemia prevalence in relation to climate covariates to predict nationwide antigenaemia prevalence. Second, we modelled clinical cases for unmapped TAs based on our antigenaemia prevalence spatial estimates.Principle findingsThe models estimated 20,938 (95% CrI 18,091 to 24,071) clinical cases in unmapped TAs (70.3%) in addition to the 8,856 (29.7%), programme-identified cases in mapped TAs. In total, the overall national number of LF clinical cases was estimated to be 29,794 (95% CrI 26,957 to 32,927). The antigenaemia prevalence and clinical case mapping and modelling found the highest burden of disease in Chikwawa and Nsanje districts in the Southern Region and Karonga district in the Northern Region of the country.ConclusionsThe models presented in this study have facilitated the development of the first national LF clinical case database and map in Malawi, the first endemic country in sub-Saharan Africa. It highlights the value of using existing LF antigenaemia prevalence and clinical case data together with modelling approaches to produce estimates that may be used for the WHO dossier requirements, to help target limited resources and implement long-term health strategies.

BackgroundLymphatic filariasis (LF) is a parasitic disease transmitted by mosquitoes, causing severe pain, disfiguring, and disabling clinical conditions such as lymphoedema and hydrocoele. LF is a global public health problem affecting 72 countries, primarily in Africa and Asia. Since 2000, the World Health Organization (WHO) has led the Global Programme to Eliminate Lymphatic Filariasis (GPELF) to support all endemic regions. This paper focuses on the achievements of the Malawi LF Elimination Programme between 2000 and 2020 to eliminate LF as a public health problem, making it the second sub-Saharan country to receive validation from the WHO.Methodology/principal findingsThe Malawi LF Programme addressed the widespread prevalence of LF infection and disease across the country, using the recommended WHO GPELF strategies and operational research initiatives in collaboration with key national and international partners. First, to stop the spread of infection (i.e., interrupt transmission) and reduce the circulating filarial antigen prevalence from as high as 74.4% to below the critical threshold of 1-2% prevalence, mass drug administration (MDA) using a two-drug regime was implemented at high coverage rates (>65%) of the total population, with supplementary interventions from other programmes (e.g., malaria vector control). The decline in prevalence was monitored and confirmed over time using several impact assessment and post-treatment surveillance tools including the standard sentinel site, spot check, and transmission assessment surveys and alternative integrated, hotspot, and easy-access group surveys. Second, to alleviate suffering of the affected populations (i.e., control morbidity) the morbidity management and disability prevention (MMDP) package of care was implemented. Specifically, clinical case estimates were obtained via house-to-house patient searching activities; health personnel and patients were trained in self-care protocols for lymphoedema and/or referrals to hospitals for hydrocoele surgery; and the readiness and quality of treatment and services were assessed with new survey tools.ConclusionsMalawi's elimination of LF will ensure that future generations are not infected and suffer from the disfiguring and disabling disease. However, it will be critical that the Malawi LF Elimination programme remains vigilant, focussing on post-elimination surveillance and MMDP implementation and integration into routine health systems to support long-term sustainability and ongoing success.SummaryLymphatic filariasis, also known as elephantiasis, is a disabling, disfiguring, and painful disease caused by a parasite that infected mosquitoes transmit to millions of people worldwide. Since 2000, the Global Programme to Eliminate Lymphatic Filariasis (GPELF) has supported endemic countries such as Malawi in south-eastern Africa, to eliminate the disease as a public health problem. The Malawi National LF Elimination Programme has worked tirelessly over the past two decades to implement the GPELF recommended strategies to interrupt the transmission with a two-drug regime, and to alleviate suffering in patients with lymphoedema and/or hydrocoele through morbidity management and disability prevention. Additionally, the LF Programme has collaborated with national and international stakeholders to implement a range of supplementary operational research projects to address outstanding knowledge gaps and programmatic barriers. In 2020, the World Health Organisation validated that Malawi had successfully eliminated LF as a public health problem, making it the second country in sub-Saharan Africa to achieve this, which is remarkable given that Malawi previously had very high infection rates. The LF Programme now remains vigilant, putting its efforts towards post-elimination surveillance and the continued implementation of care for patients with chronic conditions. Malawi's elimination of LF will ensure that future generations are not affected by this devastating disease.

Lymphatic filariasis and onchocerciasis are two major neglected tropical diseases that are responsible for causing severe disability in 50 million people worldwide, whilst veterinary filariasis (heartworm) is a potentially lethal parasitic infection of companion animals. There is an urgent need for safe, short-course curative (macrofilaricidal) drugs to eliminate these debilitating parasite infections. We investigated combination treatments of the novel anti-Wolbachia azaquinazoline small molecule, AWZ1066S, with benzimidazole drugs (albendazole or oxfendazole) in up to four different rodent filariasis infection models: Brugia malayi—CB.17 SCID mice, B. malayi—Mongolian gerbils, B. pahangi—Mongolian gerbils, and Litomosoides sigmodontis—Mongolian gerbils. Combination treatments synergised to elicit threshold (>90%) Wolbachia depletion from female worms in 5 days of treatment, using 2-fold lower dose-exposures of AWZ1066S than monotherapy. Short-course lowered dose AWZ1066S-albendazole combination treatments also delivered partial adulticidal activities and/or long-lasting inhibition of embryogenesis, resulting in complete transmission blockade in B. pahangi and L. sigmodontis gerbil models. We determined that short-course AWZ1066S-albendazole co-treatment significantly augmented the depletion of Wolbachia populations within both germline and hypodermal tissues of B. malayi female worms and in hypodermal tissues in male worms, indicating that anti-Wolbachia synergy is not limited to targeting female embryonic tissues. Our data provides pre-clinical proof-of-concept that sub-seven-day combinations of rapid-acting novel anti-Wolbachia agents with benzimidazole anthelmintics are a promising curative and transmission-blocking drug treatment strategy for filarial diseases of medical and veterinary importance.