Health impact of policies to reduce agriculture-related air pollutants in the UK: The relative contribution of change in PM2.5 exposure and diets to morbidity and mortality.

Food systems can negatively impact health outcomes through unhealthy diets and indirectly through ammonia emissions originating from agricultural production, which contribute to air pollution and consequently cardiovascular and respiratory health outcomes. In the UK, ammonia emissions from agriculture have not declined in the same way as other air pollutants in recent years. We applied a novel integrated modelling framework to assess the health impacts from six ammonia reduction scenarios to 2030: two agriculture scenarios - a "Current trends" scenario projecting current mitigation measures to reflect a low ambition future, and "High ambition mitigation" based on measures included in the Climate Change Committee's Balanced Pathway to Net Zero; three dietary scenarios - a "Business as usual" based on past trajectories, "Fiscal" applying 20% tax on meat and dairy and 20% subsidy on fruit and vegetables, and "Innovation" applying a 30% switch to plant-based alternatives; one combination of "High ambition mitigation" and "Innovation". Compared to "Current trends", the "High ambition mitigation" scenario would result in a reduction in premature mortality of 13,000, increase life years by 90,000 and reduce incidence of respiratory diseases by 270,000 cases over a 30 year period. Compared to Business as Usual, the dietary scenarios would reduce the number of premature deaths by 65,000 and 550,000-600,000 life years gained over 30 years, with most of the benefits gained by reducing ischemic heart disease (incidence reduction: 190,000). The "High ambition combination" would lead to 67,000 deaths averted, 536,000 incidence reductions and 650,000 life-years gained. For all scenarios, older age groups and those living in lower income households would experience the greatest benefits, because of higher underlying mortality rates or higher levels of risk factors. Our study shows that combining mitigation policies targeting agricultural production systems with diet-related policies would lead to significant reductions in emissions and improvement in health outcomes.

Multiligament knee injury (MLKI): an expert consensus statement on nomenclature, diagnosis, treatment and rehabilitation.

Multiligament knee injuries (MLKIs) represent a broad spectrum of pathology with potentially devastating consequences. Currently, disagreement in the terminology, diagnosis and treatment of these injuries limits clinical care and research. This study aimed to develop consensus on the nomenclature, diagnosis, treatment and rehabilitation strategies for patients with MLKI, while identifying important research priorities for further study. An international consensus process was conducted using validated Delphi methodology in line with British Journal of Sports Medicine guidelines. A multidisciplinary panel of 39 members from 14 countries, completed 3 rounds of online surveys exploring aspects of nomenclature, diagnosis, treatment, rehabilitation and future research priorities. Levels of agreement (LoA) with each statement were rated anonymously on a 5-point Likert scale, with experts encouraged to suggest modifications or additional statements. LoA for consensus in the final round were defined 'a priori' if >75% of respondents agreed and fewer than 10% disagreed, and dissenting viewpoints were recorded and discussed. After three Delphi rounds, 50 items (92.6%) reached consensus. Key statements that reached consensus within nomenclature included a clear definition for MLKI (LoA 97.4%) and the need for an updated MLKI classification system that classifies injury mechanism, extent of non-ligamentous structures injured and the presence or absence of dislocation. Within diagnosis, consensus was reached that there should be a low threshold for assessment with CT angiography for MLKI within a high-energy context and for certain injury patterns including bicruciate and PLC injuries (LoA 89.7%). The value of stress radiography or intraoperative fluoroscopy also reached consensus (LoA 89.7%). Within treatment, it was generally agreed that existing literature generally favours operative management of MLKI, particularly for young patients (LoA 100%), and that single-stage surgery should be performed whenever possible (LoA 92.3%). This consensus statement will facilitate clinical communication in MLKI, the care of these patients and future research within MLKI.

Re-entrant percolation in active Brownian hard disks.

Non-equilibrium clustering and percolation are investigated in an archetypal model of two-dimensional active matter using dynamic simulations of self-propelled Brownian repulsive particles. We concentrate on the single-phase region up to moderate levels of activity, before motility-induced phase separation (MIPS) sets in. Weak activity promotes cluster formation and lowers the percolation threshold. However, driving the system further out of equilibrium partly reverses this effect, resulting in a minimum in the critical density for the formation of system-spanning clusters and introducing re-entrant percolation as a function of activity in the pre-MIPS regime. This non-monotonic behaviour arises from competition between activity-induced effective attraction (which eventually leads to MIPS) and activity-driven cluster breakup. Using an adapted iterative Boltzmann inversion method, we derive effective potentials to map weakly active cases onto a passive (equilibrium) model with conservative attraction, which can be characterised by Monte Carlo simulations. While the active and passive systems have practically identical radial distribution functions, we find decisive differences in higher-order structural correlations, to which the percolation threshold is highly sensitive. For sufficiently strong activity, no passive pairwise potential can reproduce the radial distribution function of the active system.

No Replication of Alzheimer's Disease Genetics as a Moderator of Combat Exposure's Association with PTSD risk in 138,592 Combat Veterans.

Large-scale cohort and epidemiological studies suggest that posttraumatic stress disorder (PTSD) confers risk for late-onset Alzheimer's disease (AD) and related dementias (ADRD); however, the basis for this association remains unclear. Several prior studies of military Veterans have reported that carriers of the apolipoprotein E (APOE) ε4 gene variant are at heightened risk for the development of PTSD following combat exposure, suggesting that PTSD and ADRD may share some genetic risk. This cohort study was designed to further examine the hypothesis that ADRD genetic risk also confers risk for PTSD. To do so, we examined APOE ε4 and ε2 genotypes, an AD polygenic risk score (PRS), and other Veteran-relevant risk factors for PTSD in age-stratified groups of individuals of European (n = 123,372) and African (n = 15,220) ancestry in the US Department of Veterans Affairs' Million Veteran Program. Analyses revealed no significant main effect associations between the APOE ε4 (or ε2) genotype or the AD PRS on PTSD severity or diagnosis. There were also no significant interactions between measures of AD genetic risk and either combat exposure severity or history of head injury in association with PTSD in any age group. We conclude that the association between PTSD and the primary ADRD genetic risk factor, APOE ε4, that was reported previously was not replicable in the largest relevant dataset in the world. Thus, the epidemiological association between PTSD and ADRD is not likely to be driven by the major genetic factors underlying ADRD risk.

Trace detection of styphnate from pre- and post-blast samples by hydrophilic interaction chromatography with tandem mass spectrometry.

RATIONALE: Although ubiquitous in explosives and ammunition, few trace methods for detection of heavy metal-containing primary explosives from forensic samples are currently in practice. METHODS: Extracts of cotton swabs or direct sampling of items were cleaned up using solid-phase extraction to remove heavy metal contaminants (i.e., lead) while retaining the organic styphnate component. The styphnate was chromatographically separated using hydrophilic interaction chromatography (HILIC) and detected via high-resolution tandem mass spectrometry (MS/MS) using a sensitive, targeted approach in five minutes or less. RESULTS: A mass spectrometric method for the detection of styphnate, including limit of detection (LOD), sample stability, and interferences was developed. We present a validated method for the extraction, separation, and detection of styphnate from lead(II) styphnate with an estimated LOD of 257 ppt (pg/mL). CONCLUSIONS: We detail an improved LOD relative to previous reports for trace detection of styphnate and, for the first time to our knowledge, the post-blast analysis of styphnate.

Executive function and cortical thickness in biomarker aMCI.

INTRODUCTION: Memory deficits are the primary symptom in amnestic Mild Cognitive Impairment (aMCI); however, executive function (EF) deficits are common. The current study examined EF in aMCI based upon amyloid status (A+/A-) and regional atrophy in signature areas of Alzheimer's disease (AD). METHOD: Participants included 110 individuals with aMCI (A+ = 66; A- = 44) and 33 cognitively healthy participants (HP). EF was assessed using four neuropsychological assessment measures. The cortical thickness of the AD signature areas was calculated using structural MRI data. RESULTS: A + had greater EF deficits and cortical atrophy relative to A - in the supramarginal gyrus and superior parietal lobule. A - had greater EF deficits relative to HP, but no difference in signature area cortical thickness. DISCUSSION: The current study found that the degree of EF deficits in aMCI are a function of amyloid status and cortical thinning in the parietal cortex.

Anterior Cruciate Ligament Tears in Soccer Players.

Anterior cruciate ligament (ACL) injuries to soccer players present unique challenges in sports medicine, given the sport's global prevalence and intricate injury dynamics. These injuries, especially in the youth and female demographic, have become a substantial concern in sports medicine. This review explores the epidemiology, mechanism of injury, diagnostic procedures, treatment modalities, and rehabilitation strategies related to ACL tears within the soccer community. Progress in diagnostics, treatments, and rehabilitation underscores the importance of evidence-based approaches. As soccer continues its ascent in popularity, addressing the specific risks and nuances of ACL injuries in this context remains of paramount significance.

Zürich II Statement on Per- and Polyfluoroalkyl Substances (PFASs): Scientific and Regulatory Needs.

Per- and polyfluoroalkyl substances (PFASs) are a class of synthetic organic chemicals of global concern. A group of 36 scientists and regulators from 18 countries held a hybrid workshop in 2022 in Zürich, Switzerland. The workshop, a sequel to a previous Zürich workshop held in 2017, deliberated on progress in the last five years and discussed further needs for cooperative scientific research and regulatory action on PFASs. This review reflects discussion and insights gained during and after this workshop and summarizes key signs of progress in science and policy, ongoing critical issues to be addressed, and possible ways forward. Some key take home messages include: 1) understanding of human health effects continues to develop dramatically, 2) regulatory guidelines continue to drop, 3) better understanding of emissions and contamination levels is needed in more parts of the world, 4) analytical methods, while improving, still only cover around 50 PFASs, and 5) discussions of how to group PFASs for regulation (including subgroupings) have gathered momentum with several jurisdictions proposing restricting a large proportion of PFAS uses. It was concluded that more multi-group exchanges are needed in the future and that there should be a greater diversity of participants at future workshops.

Subjective cognitive concerns, APOE ε4, PTSD symptoms, and risk for dementia among older veterans.

BACKGROUND: Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with self-reported problems with cognition as well as risk for Alzheimer's disease and related dementias (ADRD). Overlapping symptom profiles observed in cognitive disorders, psychiatric disorders, and environmental exposures (e.g., head injury) can complicate the detection of early signs of ADRD. The interplay between PTSD, head injury, subjective (self-reported) cognitive concerns and genetic risk for ADRD is also not well understood, particularly in diverse ancestry groups. METHODS: Using data from the U.S. Department of Veterans Affairs (VA) Million Veteran Program (MVP), we examined the relationship between dementia risk factors (APOE ε4, PTSD, TBI) and subjective cognitive concerns (SCC) measured in individuals of European (n = 140,921), African (n = 15,788), and Hispanic (n = 8,064) ancestry (EA, AA, and HA, respectively). We then used data from the VA electronic medical record to perform a retrospective survival analysis evaluating PTSD, TBI, APOE ε4, and SCC and their associations with risk of conversion to ADRD in Veterans aged 65 and older. RESULTS: PTSD symptoms (B = 0.50-0.52, p < 1E-250) and probable TBI (B = 0.05-0.19, p = 1.51E-07 - 0.002) were positively associated with SCC across all three ancestry groups. APOE ε4 was associated with greater SCC in EA Veterans aged 65 and older (B = 0.037, p = 1.88E-12). Results of Cox models indicated that PTSD symptoms (hazard ratio [HR] = 1.13-1.21), APOE ε4 (HR = 1.73-2.05) and SCC (HR = 1.18-1.37) were positively associated with risk for ADRD across all three ancestry groups. In the EA group, probable TBI also contributed to increased risk of ADRD (HR = 1.18). CONCLUSIONS: The findings underscore the value of SCC as an indicator of ADRD risk in Veterans 65 and older when considered in conjunction with other influential genetic, clinical, and demographic risk factors.

Peri-operative zoledronic acid attenuates peri-prosthetic osteolysis in a rat model of cemented knee replacement.

Progressive osteolysis can occur at the cement-bone interface of joint replacements and the associated loss of fixation can lead to clinical loosening. We previously developed a rat hemiarthroplasty model that exhibited progressive loss of fixation with the development of cement-bone gaps under the tibial tray that mimicked patterns found in human arthroplasty retrievals. Here we explored the ability of a bisphosphonate (zoledronic acid, ZA) to attenuate cement-bone osteolysis and maintain implant stability. Sprague-Dawley rats (n = 59) received a poly(methylmethacrylate) cemented tibial component and were followed for up to 12 weeks. Treatment groups included peri-operative administration of ZA (ZA group), administration of ZA at 6 weeks postop (late ZA group), or vehicle (Veh group). There was a 60% reduction in the rate of cement-bone gap formation for the ZA group (0.15 mm3/week) compared to Veh group (0.38 mm3/week, p = 0.016). Late ZA prevented further progression of gap formation but did not reverse bone loss to the level achieved in the ZA group. Micromotion from five times body weight toggle loading was positively correlated with cement-bone gap volume (p = 0.009) and negatively correlated with the amount of cement in the metaphysis (p = 0.005). Reduced new bone formation and enduring nonviable bone in the epiphysis for the ZA group were found. This suggests that low bone turnover in the epiphysis may suppress the early catabolic response due to implantation, thereby maintaining better fixation in the epiphysis. This preclinical model presents compelling supporting data documenting improved maintenance of the cement-bone fixation with the use of peri-operative bisphosphonates.

Epigenome-wide association studies identify novel DNA methylation sites associated with PTSD: A meta-analysis of 23 military and civilian cohorts.

Background: The occurrence of post-traumatic stress disorder (PTSD) following a traumatic event is associated with biological differences that can represent the susceptibility to PTSD, the impact of trauma, or the sequelae of PTSD itself. These effects include differences in DNA methylation (DNAm), an important form of epigenetic gene regulation, at multiple CpG loci across the genome. Moreover, these effects can be shared or specific to both central and peripheral tissues. Here, we aim to identify blood DNAm differences associated with PTSD and characterize the underlying biological mechanisms by examining the extent to which they mirror associations across multiple brain regions. Methods: As the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, we conducted the largest cross-sectional meta-analysis of epigenome-wide association studies (EWASs) of PTSD to date, involving 5077 participants (2156 PTSD cases and 2921 trauma-exposed controls) from 23 civilian and military studies. PTSD diagnosis assessments were harmonized following the standardized guidelines established by the PGC-PTSD Workgroup. DNAm was assayed from blood using either Illumina HumanMethylation450 or MethylationEPIC (850K) BeadChips. A common QC pipeline was applied. Within each cohort, DNA methylation was regressed on PTSD, sex (if applicable), age, blood cell proportions, and ancestry. An inverse variance-weighted meta-analysis was performed. We conducted replication analyses in tissue from multiple brain regions, neuronal nuclei, and a cellular model of prolonged stress. Results: We identified 11 CpG sites associated with PTSD in the overall meta-analysis (1.44e-09 < p < 5.30e-08), as well as 14 associated in analyses of specific strata (military vs civilian cohort, sex, and ancestry), including CpGs in AHRR and CDC42BPB. Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Methylation at most CpGs correlated with their annotated gene expression levels. Conclusions: This study identifies 11 PTSD-associated CpGs, also leverages data from postmortem brain samples, GWAS, and genome-wide expression data to interpret the biology underlying these associations and prioritize genes whose regulation differs in those with PTSD.

Cortical Thickness Correlates of Go/No-go and Motor Sequencing in Mild Cognitive Impairment and Suspected Alzheimer Disease Dementia.

BACKGROUND: While the cognitive hallmark of typical Alzheimer disease (AD) is impaired memory consolidation, increasing evidence suggests that the frontal lobes and associated executive functions are also impacted. OBJECTIVE: We examined two neurobehavioral executive function tasks and associations with cortical thickness in patients diagnosed with mild cognitive impairment (MCI), suspected AD dementia, and a healthy control group. METHODS: First, we compared group performances on a go/no-go (GNG) task and on Luria's Fist-Edge-Palm (FEP) motor sequencing task. We then examined correlations between neurobehavioral task performance and the thickness of frontal cortical regions, AD signature regions, broader unbiased brain regions, and white matter hyperintensities (WMH). RESULTS: Participants with MCI performed worse than healthy controls, but better than participants with suspected AD dementia on both tasks. Both GNG and FEP (to a slightly greater extent) tasks showed diffuse associations with most AD signature regions and multiple additional regions within the temporal, parietal, and occipital cortices. Similarly, both tasks showed significant associations with all other cognitive tasks examined. Of the frontal regions examined, only the middle frontal gyrus and pars opercularis were associated with performance on these tasks. Interactions between the precuneus and transtemporal gyri were most predictive of GNG task performance, while the interaction between superior temporal and lingual gyri was most predictive of FEP task performance. CONCLUSION: This study replicates difficulties with both GNG and FEP tasks in participants with MCI and AD dementia. Both tasks showed widespread associations with the cortical thickness of various brain structures rather than localizing to frontal regions, consistent with the diffuse nature of AD.

Combined tibial deflexion osteotomy and anterior cruciate ligament reconstruction improves knee function and stability: A systematic review.

IMPORTANCE: Patients with excessive posterior tibial slope (PTS) may have higher risks of anterior cruciate ligament (ACL) reconstruction (ACL-R) failure, and clinical outcomes after revision of ACL-R procedures are typically poor. OBJECTIVE: This study aimed to perform a systematic review of the literature summarizing the clinical and radiological outcomes of the surgical treatment of ACL insufficiency in the setting of excessive PTS using a tibial deflexion osteotomy combined with ACL-R. EVIDENCE REVIEW: A systematic review of the literature was performed using PubMed, Cochrane Library, and OVID Medline databases from 1990 to present. Inclusion criteria were studies of outcomes of isolated tibial deflexion osteotomies performed with primary or revision ACL-R in the English language. Data extracted included study demographic information, type of tibial deflexion osteotomy and concomitant procedures, radiological outcomes, patient-reported outcome scores, and postoperative complications. FINDINGS: Six studies, with 133 knees were identified. All included studies were retrospective case series, with a weighted mean follow-up of 3.39 years. In 106 of 133 (79.7%) knees, tibial deflexion osteotomy was performed concomitantly with an ACL-R, whereas in 27 of 133 (20.3%) knees, the procedures were staged. 22, 45, and 66 of 133 knees (16.5%, 33.8%, and 49.6%) underwent primary, first revision, and second or greater revision ACL-R, respectively. Three of 133 (2.25%) knees demonstrated recurrent ACL graft failure at the final follow-up. On average, PTS decreased from 15.2° preoperatively to 7.1° postoperatively. The mean International Knee Documentation Committee, Lysholm, and Tegner scores increased from 42.5, 46.4, and 4.2 preoperatively to 71.8, 89.0, and 6.7 postoperatively. CONCLUSIONS: The results of this review suggest that combined ACL-R and tibial deflexion osteotomy may be effective in decreasing PTS and improving knee function and stability. STUDY DESIGN: Systematic Review; Level of evidence 4.

The effect of factors from different time points on psychological readiness following ACL reconstruction.

OBJECTIVE: The purpose of this study was to examine factors correlated with psychological readiness to return to activity after ACLR. DESIGN: cross sectional study. SETTING: controlled laboratory. PARTICIPANTS: 164 patients (82 M/82 F, 22.5 ± 8.9yr, 171.6 ± 11.0 cm, 77.4 ± 18.6 kg, 8.6 ± 3.4 months post-ACLR) participated in this study after a primary, isolated, and uncomplicated ACLR. MAIN OUTCOME MEASURES: ACL Return to Sport Index (ACL-RSI). RESULTS: ACL-RSI scores demonstrated a weak positive correlation with activity level at the time of injury and a fair positive correlation with activity level at the time of post-operative testing (p-values: 0.004, <0.001). ACL-RSI scores showed a statistically significant fair negative correlation with pain and a moderate negative correlation with kinesiophobia during rehabilitation (p-values: <0.001, <0.001). There was no statistical significance between ACL-RSI and the surgical variables (p-value range: 0.10-0.61). CONCLUSIONS: Outcomes from testing during postoperative rehabilitation were most correlated with psychological readiness to return to activity after ACLR. Increased pain and kinesiophobia were associated with a decreased psychological readiness. Increased activity level prior to injury and activity level at the time of testing during rehabilitation were both correlated with increased psychological readiness. Psychological readiness to return to activity may need to be customized based on potentially modifiable patient-specific factors during the post-operative rehabilitation.

Environmentally Not So Friendly: Global Warming, Air Pollution, and Wildfires: JACC Focus Seminar, Part 1.

Environmental stresses are increasingly recognized as significant risk factors for adverse health outcomes. In particular, various forms of pollution and climate change are playing a growing role in promoting noncommunicable diseases, especially cardiovascular disease. Given recent trends, global warming and air pollution are now associated with substantial cardiovascular morbidity and mortality. As a vicious cycle, global warming increases the occurrence, size, and severity of wildfires, which are significant sources of airborne particulate matter. Exposure to wildfire smoke is associated with cardiovascular disease, and these effects are underpinned by mechanisms that include oxidative stress, inflammation, impaired cardiac function, and proatherosclerotic effects in the circulation. In the first part of a 2-part series on pollution and cardiovascular disease, this review provides an overview of the impact of global warming and air pollution, and because of recent events and emerging trends specific attention is paid to air pollution caused by wildfires.

Water, Soil, Noise, and Light Pollution: JACC Focus Seminar, Part 2.

Various forms of pollution carry a substantial burden with respect to increasing the risk of causing and exacerbating noncommunicable diseases, especially cardiovascular disease. The first part of this 2-part series on pollution and cardiovascular disease provided an overview of the impact of global warming and air pollution. This second paper provides an overview of the impact of water, soil, noise, and light pollution on the cardiovascular system. This review discusses the biological mechanisms underlying these effects and potential environmental biometrics of exposure. What is clear from both these pollution papers is that significant efforts and redoubled urgency are needed to reduce the sources of pollution in our environment, to incorporate environmental risk factors into medical education, to provide resources for research, and, ultimately, to protect those who are particularly vulnerable and susceptible.

Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood.

The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) included the central nucleus of the amygdala, hippocampal dentate gyrus, and medial prefrontal cortex (mPFC). Genes and exons within the mPFC carried most disease signals replicated across two independent cohorts. Pathways pointed to immune function, neuronal and synaptic regulation, and stress hormones. Multiomic factor and gene network analyses provided the underlying genomic structure. Single nucleus RNA sequencing in dorsolateral PFC revealed dysregulated (stress-related) signals in neuronal and non-neuronal cell types. Analyses of brain-blood intersections in >50,000 UK Biobank participants were conducted along with fine-mapping of the results of PTSD and MDD genome-wide association studies to distinguish risk from disease processes. Our data suggest shared and distinct molecular pathology in both disorders and propose potential therapeutic targets and biomarkers.

More People, More Active, More Often for Heart Health - Taking Action on Physical Activity.

Physical inactivity is a leading contributor to increased cardiovascular morbidity and mortality. Almost 500 million new cases of preventable noncommunicable diseases (NCDs) will occur globally between 2020 and 2030 due to physical inactivity, costing just over US$300 billion, or around US$ 27 billion annually (WHO 2022). Active adults can achieve a reduction of up to 35% in risk of death from cardiovascular disease. Physical activity also helps in moderating cardiovascular disease risk factors such as high blood pressure, unhealthy weight and type 2 diabetes. For people with cardiovascular disease, hypertension, type 2 diabetes and many cancers, physical activity is an established and evidence-based part of treatment and management. For children and young people, physical activity affords important health benefits. Physical activity can also achieve important cross-sector goals. Increased walking and cycling can reduce journeys by vehicles, air pollution, and traffic congestion and contribute to increased safety and liveability in cities.