The association of painful and non-painful morbidities with frailty: a cross sectional analysis of a cohort of community dwelling older people in England.

INTRODUCTION: The association between chronic pain and frailty might indicate that pain is an independent driver of frailty but might alternatively be explained by inclusion within frailty identification tools of morbidities that commonly lead to chronic pain. This research examines the extent to which the association of pain with frailty might be attributed to morbidities. METHODS: A cross-sectional analysis of older people in a UK cohort with or at risk of musculoskeletal problems or frailty (Investigating Musculoskeletal Health and Wellbeing study), used multivariable logistic regression and Z-tests to assess the degrees of associations of pain (McGill Pain Rating Index), and painful and non-painful morbidity counts with frailty (modified FRAIL questionnaire). RESULTS: Data were from 2,185 participants, 56% female, median age 73 (range 60 to 96) years. 430 (20%) participants were classified as frail. In a fully adjusted standardised model, pain (aOR 2.07 (95%CI 1.83 to 2.33) and 'any' morbidity aOR (1.74 (95%CI 1.54 to 1.97) were both significantly associated with frailty. When morbidity was subclassified as painful or non-painful, painful (aOR 1.48 (95%CI 1.30 to 1.68) and non-painful (aOR1.39 (95%CI 1.24 to 1.56)) morbidities each were associated with frailty, as also was pain (aOR 2.07 (95%CI 1.83 to 2.34, p < 0.001). CONCLUSIONS: Pain is associated with frailty, over and above any effect of painful and non-painful morbidities. This forms the justification for future research which focuses on pain management in the identification, prevention, and treatment of frailty.

Cumulative Effects of Watershed Disturbances and Run-of-river Dams on Mercury Cycling: Case Study and Recommendations for Environmental Managers.

Run-of-river power plants (ROR) represent the majority of hydroelectric plants worldwide. Their environmental impacts are not well documented and are believed to be limited, particularly regarding the contamination of food webs by methylmercury (MeHg), a neurotoxin. RORs are typically installed in small rivers where combined effects of watershed disturbances with dam construction can complicate environmental management. We report a multi-year case study on the Saint-Maurice River (Canada) where an unpredicted temporary increase in MeHg accumulation in predator fish was observed after the construction of two ROR plants. The associated pondages acted as sedimentation basins for mercury (Hg) and organic matter from a watershed disturbed by a forest fire and by logging. This fresh organic carbon likely fueled microbial MeHg production. Hg methylation was more associated with environmental conditions than to the presence of Hg, and main methylating microbial groups were identified. A constructed wetland was a site of significant Hg methylation but was not the main source of the fish Hg increase. Organic carbon degradation was the main driver of MeHg accumulation at the base of the food chain whereas trophic levels explained the variations at the top of the food chain. Overall, carbon cycling was a key driver of Hg dynamics in this system, and ROR plants can cause temporary (ca. 12 years) Hg increase in food webs when developed in disturbed watersheds, although this increase is smaller than for large reservoirs. Recommendations for future ROR construction are to establish a good environmental monitoring plan with initial high temporal resolution and to consider recent and potential watershed disturbances in the plan.

Osteoarthritis Bone Marrow Lesions.

Assessment and treatment of Bone Marrow Lesions (BMLs) could ultimately make step changes to the lives of people with osteoarthritis (OA). We here review the imaging and pathological characteristics of OA-BMLs, their differential diagnosis and measurement, and cross-sectional and longitudinal associations with pain and OA structural progression. We discuss how biomechanical and cellular factors may contribute to BML pathogenesis, and how pharmacological and non-pharmacological interventions that target BMLs might reduce pain and OA structural progression. We critically appraise semiquantitative and quantitative methods for assessing BMLs, and their potential utilities for identifying people at risk of symptomatic and structural OA progression, and evaluating treatment responses. New interventions that target OA-BMLs should both confirm their importance, and reduce the unacceptable burden of OA.

Harmonising knee pain patient-reported outcomes: a systematic literature review and meta-analysis of Patient Acceptable Symptom State (PASS) and individual participant data (IPD).

OBJECTIVE: In order to facilitate data pooling between studies, we explored harmonisation of patient-reported outcome measures (PROMs) in people with knee pain due to osteoarthritis or knee trauma, using the Patient Acceptable Symptom State scores (PASS) as a criterion. METHODS: We undertook a systematic literature review (SLR) of PASS scores, and performed individual participant data (IPD) analysis of score distributions from concurrently completed PROM pairs. Numerical rating scales (NRS), visual analogue scales, KOOS and WOMAC pain questionnaires were standardised to 0 to 100 (worst) scales. Meta-regression explored associations of PASS. Bland Altman plots compared PROM scores within individuals using IPD from WebEx, KICK, MenTOR and NEKO studies. RESULTS: SLR identified 18 studies reporting PASS in people with knee pain. Pooled standardised PASS was 27 (95% CI: 21 to 35; n = 6,339). PASS was statistically similar for each standardised PROM. Lower PASS was associated with lower baseline pain (ß = 0.49, P = 0.01) and longer time from treatment initiation (Q = 6.35, P = 0.04). PASS scores were lowest in ligament rupture (12, 95% CI: 11 to 13), but similar between knee osteoarthritis (31, 95% CI: 26 to 36) and meniscal tear (27, 95% CI: 20 to 35). In IPD, standardised PROMs each revealed similar group mean scores, but scores within individuals diverged between PROMs (LoA between -7 to -38 and +25 to 52). CONCLUSION: Different standardised PROMs give similar PASS thresholds in group data. PASS thresholds may be affected more by patient and treatment characteristics than between PROMs. However, different PROMs give divergent scores within individuals, possibly reflecting different experiences of pain.

A metagenomic-based study of two sites from the Barbadian reef system.

We study the microbiome of sea water collected from two locations of the Barbadian coral reefs. The two sites differ in several environmental and ecological variables including their endogenous benthic community and their proximity to urban development and runoffs from inland watersheds. The composition of the microbial communities was estimated using whole genome DNA shotgun sequencing with adjuvant measurements of chemical and environmental qualities. Although both sites exhibit a similar degree of richness, the less urbanized site (Maycocks reef at Hangman's Bay) has a strong concentration of phototrophs whereas the more urbanized location (Bellairs reef at Folkstone) is enriched for copiotrophs, macroalgal symbionts and marine-related disease-bearing organisms from taxa scattered across the tree of life. Our results are concordant with previous profiles of warm ocean surface waters, suggesting our approach captures the state of each coral reef site, setting the stage for longitudinal studies of marine microbiome dynamics in Barbados. Supplementary Information: The online version contains supplementary material available at 10.1007/s00338-022-02330-y.

Wildlife health surveillance: gaps, needs and opportunities.

Disease emergence represents a global threat to public health, economy and biological conservation. Most emerging zoonotic diseases have an animal origin, most commonly from wildlife. To prevent their spread and to support the implementation of control measures, disease surveillance and reporting systems are needed, and due to globalisation, these activities should be carried out at the global level. To define the main gaps affecting the performance of wildlife health surveillance and reporting systems globally, the authors analysed data from a questionnaire sent to National Focal Points of the World Organisation for Animal Health that inquired on structure and limits of wildlife surveillance and reporting systems in their territories. Responses from 103 Members, covering all areas of the globe, revealed that 54.4% have a wildlife disease surveillance programme and 66% have implemented a strategy to manage disease spread. The lack of dedicated budget affected the possibility of outbreak investigations, sample collection and diagnostic testing. Although most Members maintain records relating to wildlife mortality or morbidity events in centralised databases, data analysis and disease risk assessment are reported as priority needs. The authors' evaluation of surveillance capacity found an overall low level, with marked variability among Members that was not restricted to a specific geographical area. Increased wildlife disease surveillance globally would help in understanding and managing risks to animal and public health. Moreover, consideration of the influence of socio-economic, cultural and biodiversity aspects could improve disease surveillance under a One Health approach.

L'émergence de maladies représente une menace pour la santé publique, l'économie et la conservation de la biodiversité au niveau mondial. La plupart des maladies émergentes sont d'origine animale et proviennent de la faune sauvage. Afin de prévenir leur propagation et de soutenir la mise en oeuvre de mesures de contrôle, une surveillance des maladies et des systèmes de notification sont nécessaires - et ce à l'échelle internationale, en raison de la mondialisation. En vue de définir les lacunes principales affectant les performances de la surveillance et de la notification sanitaire relative à la faune sauvage au niveau mondial, les auteurs ont analysé les données d'un questionnaire envoyé aux Points focaux nationaux de l'Organisation mondiale de la santé animale et traitant de la structure et des limites des systèmes de surveillance et de notification applicables à la faune sauvage sur leur territoire. Selon les réponses des 103 Membres, qui représentaient toutes les régions du monde, 54,4 % disposent d'un programme de surveillance et 66 % ont mis en oeuvre une stratégie visant à gérer la propagation de maladies. L'absence de budgets dédiés affecte la possibilité d'enquêter sur l'apparition d'épidémies, de prélever des échantillons et d'effectuer des tests diagnostiques. Bien que la majorité des Membres consignent dans des bases de données centralisées les événements de mortalité et de morbidité affectant la faune sauvage, l'analyse des données et l'évaluation des risques sanitaires ont été mentionnées comme étant des besoins prioritaires. Les auteurs ont évalué les capacités de surveillance qui se situent, selon eux, à un niveau faible et se caractérisent par une grande variabilité entre les Membres, indépendamment des zones géographiques dont il s'agit. Une meilleure surveillance sanitaire de la faune sauvage au niveau mondial permettrait d'améliorer la compréhension et la gestion des risques pour la santé animale et publique. Par ailleurs, une réflexion sur l'influence des aspects socio-économiques, culturels et liés à la biodiversité améliorerait la surveillance sanitaire mise en place dans le cadre de l'approche Une seule santé.

La aparición de enfermedades representa una amenaza de dimensión mundial para la salud pública, la economía y la conservación de los recursos biológicos. La mayor parte de las enfermedades zoonóticas tienen un origen animal, por lo general localizado en la fauna silvestre. Para evitar que estas enfermedades se propaguen y apoyar la aplicación de medidas de lucha hacen falta sistemas de vigilancia y notificación de enfermedades, sistemas que, teniendo en cuenta las dinámicas de la mundialización, deben declinarse a escala planetaria. Con objeto de determinar las principales carencias que lastran el buen funcionamiento de los sistemas de vigilancia y notificación de enfermedades de la fauna silvestre a escala mundial, los autores analizaron datos extraídos de un cuestionario distribuido entre los puntos focales nacionales de la Organización Mundial de Sanidad Animal, en el cual se les preguntaba por la estructura y los límites que presentaban en su territorio dichos sistemas. Las respuestas recibidas de 103 Miembros de todas las zonas del globo pusieron de relieve que un 54,4% de ellos cuenta con un programa de vigilancia sanitaria de la fauna silvestre y que un 66% tiene implantada una estrategia para contener la propagación de enfermedades. La falta de un presupuesto asignado específicamente a estas tareas limita la posibilidad de investigar eventuales brotes, obtener muestras y practicar pruebas de diagnóstico. Aunque la mayoría de los Miembros lleva un registro de los episodios de mortalidad y morbilidad de animales salvajes en bases de datos centralizadas, el análisis de datos y la determinación del riesgo de enfermedad son dos de los aspectos mencionados como necesidad prioritaria. La evaluación de la capacidad de vigilancia realizada por los autores puso de manifiesto un nivel en general bajo, con una marcada heterogeneidad entre los Miembros que no se circunscribía a una zona geográfica en particular. Una mayor vigilancia de las enfermedades de la fauna silvestre a escala mundial ayudaría a aprehender y manejar mejor los riesgos que estas presentan para la sanidad animal y la salud pública. Además, el hecho de tener en cuenta la influencia de factores socioeconómicos, culturales y ligados a la diversidad biológica podría traducirse en una más eficaz vigilancia sanitaria en clave de Una sola salud.

How important is it to avoid indices of deprivation that include health variables in analyses of health inequalities?

OBJECTIVES: This study aimed to quantify the difference in mortality inequalities using the Scottish Index of Multiple Deprivation (SIMD) and the Income and Employment Index (IEI; a subindex of SIMD, which excludes health) as ranking measures in Scotland. STUDY DESIGN: This ecological study was a cross-sectional analysis of routine administrative data. METHODS: Data from the 2020 SIMD and the subindex using data from only the Income and Employment domains, the IEI, were obtained. The correlation between data zones, percentage of data zones that changed deprivation tenth and differences in the Slope Index of Inequality (SII) and Relative Index of Inequality (RII) for Standardised Mortality Ratios (SMRs) across tenths were compared when data zones were ranked by SIMD and IEI. RESULTS: There was a close correlation between data zones ranked by SIMD and IEI (R2 = 0.96). When data zones were ranked by IEI, 18.7% of data zones moved to a lower deprivation tenth, and 20.8% of data zones moved to a higher deprivation tenth, compared with SIMD. However, only a negligible number of data zones moved two or more tenths. The SMRs across deprivation tenths were very similar between the SIMD and IEI, as were the summary health inequality measures of SII (87.3 compared with 85.7) and RII (0.88 and 0.86). CONCLUSION: Although there is a logical problem in using deprivation indices that include health outcomes to rank areas to calculate the scale of health inequalities, the impact of using an alternative subindex containing only data from the income and employment domains is minimal. For population-wide analyses of health inequalities in Scotland, the SIMD does not introduce a substantial bias in the health inequalities summary measures despite substantial movement of small areas between ranked population tenths. Although not examined here, this is likely to be relevant to other similar indices across the United Kingdom.

How well do area-based deprivation indices identify income- and employment-deprived individuals across Great Britain today?

BACKGROUND: Area-based deprivation indices are used in many countries to target interventions and policies to populations with the greatest needs. Analyses of the Carstairs deprivation index applied to postcode sectors in 2001 identified that less than half of all deprived individuals lived in the most deprived areas. OBJECTIVE: This article examines the specificity and sensitivity of deprivation indices across Great Britain in identifying individuals claiming income- and employment-related social security benefits. STUDY DESIGN: This was a descriptive analysis of cross-sectional administrative data. METHODS: The data sets for the 2020 Scottish Index of Multiple Deprivation, Scottish Income and Employment Index, the 2019 English Index of Multiple Deprivation and the 2019 Welsh Index of Multiple Deprivation were obtained. For each data set, small areas were ranked by increasing overall deprivation, and the cumulative proportions of individuals who were income and employment deprived were calculated. Receiver operating characteristic curves were plotted to show the sensitivity and specificity of each index, and the percentages of income- and employment-deprived individuals captured at different overall deprivation thresholds were calculated. RESULTS: Across all indices, the sensitivity and specificity for detecting income- and employment-deprived individuals were low, with less than half living in the most deprived 20% of areas. Between 55% and 62% of income-deprived people and between 56% and 63% of employment-deprived people were missed across the indices at the 20% deprivation threshold. The sensitivity and specificity were slightly higher for income deprivation than employment deprivation across indices and slightly higher for the Scottish Index of Multiple Deprivation and Scottish Income and Employment Index than for the English Index of Multiple Deprivation and Welsh Index of Multiple Deprivation. CONCLUSION: Area-based deprivation measures in Great Britain have limited sensitivity and specificity for identifying individuals who are income or employment deprived. Place-based policies and interventions are unlikely to be effective at reducing inequalities as a result. Creation of individually linked data sets and interventions that recognise the social and economic relationships between social groups are likely to be more effective.

Time course and localization of nerve growth factor expression and sensory nerve growth during progression of knee osteoarthritis in rats.

OBJECTIVES: Nerve growth factor (NGF) and sensory nerves are key factors in established osteoarthritis (OA) knee pain. We investigated the time course of NGF expression and sensory nerve growth across early and late stages of OA progression in rat knees. DESIGN: Knee OA was induced by medial meniscectomy in rats. OA histopathology, NGF expression, and calcitonin gene-related peptide immunoreactive (CGRP-IR) nerves were quantified pre-surgery and post-surgery at weeks 1, 2, 4 and 6. Pain-related behavior was evaluated using dynamic weight distribution and mechanical sensitivity of the hind paw. RESULTS: NGF expression in chondrocytes increased from week 1 and remained elevated until the advanced stage. In synovium, NGF expression increased only in early stages, whereas in osteochondral channels and bone marrow, NGF expression increased in the later stages of OA progression. CGRP-IR nerve density in suprapatellar pouch peaked at week 4 and decreased at week 6, whereas in osteochondral channels and bone marrow, CGRP-IR innervation increased through week 6. Percent ipsilateral weight-bearing decreased throughout the OA time course, whereas reduced paw withdrawal thresholds were observed only in later stages. CONCLUSION: During progression of knee OA, time-dependent alterations of NGF expression and CGRP-IR sensory innervation are knee tissue specific. NGF expression increased in early stages and decreased in advanced stage in the synovium but continued to increase in osteochondral channels and bone marrow. Increases in CGRP- IR sensory innervation followed increases in NGF expression, implicating that NGF is a key driver of articular nerve growth associated with OA pain.

The osteoarthritis bone score (OABS): a new histological scoring system for the characterisation of bone marrow lesions in osteoarthritis.

OBJECTIVES: Bone marrow lesions (BMLs) are associated with pain in osteoarthritis (OA), but histological scores for OA focus on cartilage pathology. We developed a new scoring system, the Osteoarthritis Bone Score (OABS), to characterise OA-related BMLs. METHODS: BML/non-BML tissues identified by Magnetic Resonance Imaging (MRI) in 10 knee OA subjects were harvested at total knee replacement (TKR). Osteochondral tissue from a further 140 TKR and 23 post-mortem (PM) cases was assessed. Histological features distinguishing MRI-defined BML/non-BML tissues on qualitative analysis were classified as present (0) or absent (1), summated for the OABS, validated by Rasch analysis and sensitivity to distinguish between sample groups. Immunohistochemistry for PGP9.5 assessed innervation. RESULTS: Subchondral characteristics associated with BML tissues were cysts, fibrosis, hypervascularity, cartilage islands, trabecular thickening, loss of tidemark integrity and inflammatory cell infiltration. PGP9.5 immunoreactive perivascular nerves were associated with BMLs. OABS performed well as a measurement tool, displayed good reliability (Cronbach alpha = 0.68), had a 2-factor structure (trabecular/non-trabecular), with moderate correlation between the two factors (r = 0.56, 95% CI 0.46, 0.65). OABS scores were higher in TKR than PM cases with chondropathy, median difference 1.5 (95% CI -2, 0). OABS and Mankin scores similarly distinguished TKR from non-OA controls, but only OABS was higher in BML than non-BML tissues, median difference -4 (95% CI -5 to -2). CONCLUSIONS: OABS identifies and validly quantifies histopathological changes associated with OA BMLs. Histopathology underlying BMLs may represent 2 inter-related pathological processes affecting trabecular/non-trabecular structures. Increased vascularity/perivascular innervation in BMLs might contribute to pain.

Economics of timed artificial insemination with unsorted or sexed semen in a high-producing, pasture-based dairy production system.

This study used a stochastic simulation model to estimate the potential economic benefit of using timed artificial insemination (TAI) in combination with conventional unsorted (TCONV) and sexed (TSEX) semen in heifers only (TCONV-H, TSEX-H) and in both heifers and lactating cows (TCONV-HC, TSEX-HC) in a high-producing, pasture-based production system. The scenarios were compared with a conventional reproductive policy (CONV) in which heifers and cows were inseminated with conventional unsorted semen after estrus detection. Sensitivity analysis was also used to estimate the effect of hormone costs from TAI use on the profitability of each program relative to CONV. The mean annual (± standard deviation) profit advantage (ΔPROF) over CONV for TCONV-H, TCONV-HC, TSEX-H, and TSEX-HC scenarios were €3.90/cow ± 4.65, €34.11/cow ± 25.69, €13.96/cow ± 6.83, and €41.52/cow ± 42.86, respectively. Combined application of both technologies was shown to return a greater annual ΔPROF on average compared with that achievable from TAI alone. However, the risk of not returning a positive annual ΔPROF varied across the scenarios with higher risk in TCONV-H and TSEX-HC. Specifically, TCONV-H and TSEX-HC had a 24 and 18% chance, respectively, of not returning a positive annual ΔPROF. Sensitivity analysis showed that when hormone costs increased by €10/cow TCONV-H and TSEX-HC had a 38 and 23% chance, respectively, of not returning a positive annual ΔPROF. The range in ΔPROF for TCONV policies was most sensitive to the TAI pregnancy rate and TSEX policies were most sensitive to the relative fertility achieved with sexed compared with unsorted semen. This study has shown TAI and sexed semen are complementary technologies that can increase genetic gain and profitability in a pasture-based, dairy production system.

Blood Pressure, Orthostatic Hypotension and Falls in Patients with Advanced Cancer.

Aim Orthostatic Hypotension (OH) is an indicator of deteriorating autonomic dysfunction. Adherence to BP and OH measurement guidelines in an inpatient specialist palliative care unit (SPCU) was unknown. Compliance of BP and OH measurement in an advanced cancer cohort was audited. Methods A retrospective analysis of four consecutive months of patients admitted with an advanced cancer diagnosis to the inpatient SPCU was conducted. Data was obtained from 168 clinical records, and audited against current institutional clinical standards. Results Falls risk screening including BP and OH measurements were not measured on admission in 19% (n=32) cases as recommended by institutional guidelines. Where falls risks were identified in 94 (69%) patients only 71 (76%) of these had completed risk assessments. OH testing was incomplete or not conducted in 59% (n=42) of risk assessments. This had patient care and safety implications e.g. under-reporting falls risk. In addition, institutional guidelines were inflexible in clinical practice specific to a palliative care cohort of patient. Conclusions Institutional guidelines need regular reviewing. In cases where a healthcare professional determines it is inappropriate to perform an assessment, we recommend a modification to the tools allowing for recording of this decision. OH is an underestimated reality in hospice populations and the impact on hospice services is worthy of further study.

The Central Aspects of Pain in the Knee (CAP-Knee) questionnaire; a mixed-methods study of a self-report instrument for assessing central mechanisms in people with knee pain.

OBJECTIVES: Pain is the prevailing symptom of knee osteoarthritis. Central sensitisation creates discordance between pain and joint pathology. We previously reported a Central Pain Mechanisms trait derived from eight discrete characteristics: Neuropathic-like pain, Fatigue, Cognitive-impact, Catastrophising, Anxiety, Sleep disturbance, Depression, and Pain distribution. We here validate and show that an 8-item questionnaire, Central Aspects of Pain in the Knee (CAP-Knee) is associated both with sensory- and affective- components of knee pain severity. METHODS: Participants with knee pain were recruited from the Investigating Musculoskeletal Health and Wellbeing study in the East Midlands, UK. CAP-Knee items were refined following cognitive interviews. Psychometric properties were assessed in 250 participants using Rasch-, and factor-analysis, and Cronbach's alpha. Intra-class correlation coefficients tested repeatability. Associations between CAP-Knee and McGill Pain questionnaire pain severity scores were assessed using linear regression. RESULTS: CAP-Knee targeted the knee pain sample well. Cognitive interviews indicated that participants interpreted CAP-Knee items in diverse ways, which aligned to their intended meanings. Fit to the Rasch model was optimised by rescoring each item, producing a summated score from 0 to 16. Internal consistency was acceptable (Cronbach's alpha = 0.74) and test-retest reliability was excellent (ICC2,1 = 0.91). Each CAP-Knee item contributed uniquely to one discrete 'Central Mechanisms trait' factor. High CAP-Knee scores associated with worse overall knee pain intensity, and with each of sensory- and affective- McGill Pain Questionnaire scores. CONCLUSION: CAP-Knee is a simple and valid self-report questionnaire, which measures a single 'Central Mechanisms' trait, and may help identify and target centrally-acting treatments aiming to reduce the burden of knee pain.

Effects of herd fertility on the economics of sexed semen in a high-producing, pasture-based dairy production system.

This study used a stochastic simulation model to estimate the potential economic benefit of using sexed semen in heifers only and in heifers and lactating cows in a high-producing, pasture-based system under 3 fertility scenarios. Three breeding strategies were modeled: (1) only heifers inseminated with sexed semen and cows inseminated with conventional unsexed semen (SSH); (2) both heifers and cows inseminated with sexed semen (SSHC); and (3) a reference scenario in which all females were inseminated with conventional, unsexed semen (CONV). Each scenario was evaluated under 3 herd fertility states: high (HF), medium (MF), and low (LF), which, under the reference scenario, corresponded to herd replacement rates of 21, 25, and 31%, respectively. The model estimated the economic profit, including the net present value of the genetic gain from selection intensity. The economic return from adoption of sexed semen strategies declined, with reduced levels of baseline herd fertility turning negative in the LF state. The mean (±SD) sexed semen advantage (SSA) per cow for HF-SSH, MF-SSH, and LF-SSH scenarios were €30.61 ± 8.98, €27.45 ± 7.19, and €14.69 ± 11.06, respectively. However, the SSA per cow for HF-SSHC, MF-SSHC, and LF-SSHC scenarios were €49.14 ± 15.43, €18.46 ± 30.08, and -€19.30 ± 57.11. The range in economic profit for SSA for SSH was most sensitive to calf prices in HF-SSH and the pregnancy rate of sexed semen as a percentage of conventional unsorted semen in MF-SSH and LF-SSH. The range in economic profit for SSA for SSHC scenarios was most sensitive to the pregnancy rate of sexed semen as a percentage of conventional unsorted semen in HF-SSHC, MF-SSHC, and LF-SSHC. This study highlights the effect of baseline herd fertility state on the financial advantage of adopting sexed semen in a pasture-based dairy production system.

Cognitive assessment using the Rapid Assessment for Developmental Disabilities, Second Edition (RADD-2).

BACKGROUND: Individuals with developmental disabilities (DD) often have severe impairments and maladaptive behaviours that make it difficult to reliably assess their cognitive abilities. Given these challenges, the Rapid Assessment of Developmental Disabilities, Second Edition (RADD-2), was designed to measure general cognitive ability in this population. The purpose of this study is to demonstrate the battery's psychometric properties when used with individuals with DD who have challenging behavioural and psychiatric conditions and for those who have limited verbal skills. METHOD: The cognitive and adaptive behaviour skills of 193 children and adults with DD and considerable medical, behavioural and/or psychiatric problems were evaluated using the first and second editions of the RADD, Kaufmann Brief Intelligence Test - 2nd Edition, and Scales of Independent Behaviour - Revised Edition. Medication side effects and challenging behaviours were assessed using the Aberrant Behaviour Checklist. RESULTS: There were no floor or ceiling effects on the RADD-2. Both the nonverbal index and total scores had strong concurrent validity with other abbreviated tests of intellectual ability and good discriminant validity from measures of adaptive behaviour and medication side effects. RADD-2 scores also had strong criterion validity as they successfully differentiated between all levels of intellectual functioning. Age and sex did not differentially affect RADD-2 performance, and the co-occurrence of psychiatric conditions did not negatively affect performance. The only medical condition associated with lower RADD-2 performance was epilepsy. CONCLUSIONS: The RADD-2 can quantify the differential cognitive abilities of individuals with DD, even for those with minimal communication skills, challenging behaviours or severe medication side effects that can typically complicate assessment. This brief cognitive battery can be used to measure changes due to interventions, on the one hand, and progression of neurological disease, on the other.

Excess mortality in Glasgow: further evidence of 'political effects' on population health.

OBJECTIVES: The aim of the study was to update previous analyses of 'excess mortality' in Glasgow (Scotland) relative to the similar postindustrial cities of Liverpool and Manchester (England). The excess is defined as mortality after adjustment for socio-economic deprivation; thus, we sought to compare changes over time in both the deprivation profiles of the cities and the levels of deprivation-adjusted mortality in Glasgow relative to the other cities. This is important not only because the original analyses are now increasingly out of date but also because since publication, important (prepandemic) changes to mortality trends have been observed across all parts of the United Kingdom. STUDY DESIGN AND METHODS: Replicating as far as possible the methods of the original study, we developed a three-city deprivation index based on the creation of spatial units in Glasgow that were of similar size to those in Liverpool and Manchester (average population sizes of approximately 1600, 1500 and 1700 respectively) and an area-based measure of 'employment deprivation'. Mortality and matching population data by age, sex and small area were obtained from national agencies for two periods: 2003-2007 (the period covered by the original study) and 2014-2018. The rates of employment deprivation for each city's small areas were calculated for both periods. Indirectly standardised mortality ratios (SMRs) were calculated for Glasgow relative to Liverpool and Manchester, standardised by age and three-city deprivation decile. For context, city-level trends in age-standardised mortality rates by year, sex and city were also calculated. RESULTS: There was evidence of a stalling of improvement in mortality rates in all three cities from the early 2010s. After adjustment for area deprivation, all-cause mortality in Glasgow in 2014-2018 was c.12% higher than in Liverpool and Manchester for all ages (SMR 112.4, 95% CI 111.1-113.6) and c.17% higher for deaths under 65 years (SMR 117.1, 95% CI 114.5-119.7). The excess was higher for males (17% compared with 9% for deaths at all ages; 25% compared with 5% for 0-64 years) and for particular causes of death such as suicide and drug-related and alcohol-related causes. The results were broadly similar to those previously described for 2003-2007, although the excess for premature mortality was notably lower. In part, this was explained by changes in levels of employment deprivation, which had decreased to a greater degree in the English cities: this was particularly true of Manchester (a reduction of -43%, compared with -38% in Liverpool and -31% in Glasgow) where the overall population size had also increased to a much greater extent than in the other cities. CONCLUSIONS: High levels of excess mortality persist in Glasgow. With the political causes recently established - the excess is a 'political effect', not a 'Glasgow effect' - political solutions are required. Thus, previously published recommendations aimed at addressing poverty, inequality and vulnerability in the city are still highly relevant. However, given the evidence of more recent, UK-wide, political effects on mortality - widening mortality inequalities resulting from UK Government 'austerity' measures - additional policies at UK Government level to protect, and restore, the income of the poorest in society are also urgently needed.

Contribution of nerves within osteochondral channels to osteoarthritis knee pain in humans and rats.

OBJECTIVES: Subchondral bone may contribute to knee osteoarthritis (OA) pain. Nerve growth factor (NGF) can stimulate nerve growth through TrkA. We aimed to identify how sensory nerve growth at the osteochondral junction in human and rat knees associates with OA pain. METHODS: Eleven symptomatic chondropathy cases were selected from people undergoing total knee replacement for OA. Twelve asymptomatic chondropathy cases who had not presented with knee pain were selected post-mortem. OA was induced in rat knees by meniscal transection (MNX) and sham-operated rats were used as controls. Twice-daily oral doses (30 mg/kg) of TrkA inhibitor (AR786) or vehicle were administered from before and up to 28 days after OA induction. Joints were analysed for macroscopic appearances of articular surfaces, OA histopathology and calcitonin gene-related peptide-immunoreactive (CGRP-IR) sensory nerves in medial tibial plateaux, and rats were assessed for pain behaviors. RESULTS: The percentage of osteochondral channels containing CGRP-IR nerves in symptomatic chondropathy was higher than in asymptomatic chondropathy (difference: 2.5% [95% CI: 1.1-3.7]), and in MNX-than in sham-operated rat knees (difference: 7.8% [95%CI: 1.7-15.0]). Osteochondral CGRP-IR innervation was significantly associated with pain behavior in rats. Treatment with AR786 prevented the increase in CGRP-IR nerves in osteochondral channels and reduced pain behavior in MNX-operated rats. Structural OA was not significantly affected by AR786 treatment. CONCLUSIONS: CGRP-IR sensory nerves within osteochondral channels are associated with pain in human and rat knee OA. Reduced pathological innervation of the osteochondral junction might contribute to analgesic effects of reduced NGF activity achieved by blocking TrkA.

Patient preferences for osteoarthritis pain and chronic low back pain treatments in the United States: a discrete-choice experiment.

OBJECTIVE: To quantify preferences for attributes of potential analgesic treatments for moderate-to-severe pain associated with osteoarthritis (OA) and/or chronic low back pain (CLBP) as relevant to injectable nerve growth factor (NGF)-inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids. METHODS: We used a discrete-choice experiment (DCE) to elicit preferences for attributes of OA and CLBP pharmaceutical treatments, and a best-worst scaling (BWS) exercise to further characterize the relative importance of treatment-related side-effect risks. The survey was completed online by 602 US residents with self-reported chronic, moderate-to-severe OA pain and/or CLBP who had tried, had contraindications for, or were unwilling to take currently available pharmaceutical therapies. In the DCE, respondents repeatedly chose between two hypothetical treatments defined by six attributes (symptom control; treatment-related risks of (1) severe joint problems, (2) heart attack, and (3) physical dependence; mode/frequency of administration; and cost). In the BWS exercise, respondents evaluated ten side-effect risks. Random-parameters logit models were estimated; conditional relative attribute importance, maximum acceptable risks, and willingness to pay were calculated. RESULTS: The most important DCE attributes were improving symptom control (scaled conditional relative importance, 10.00) and reducing risk of physical dependence (6.99). The three most important BWS attributes were, in rank order, risks of stroke, physical dependence, and heart attack. Respondents were willing to accept a > 4% treatment-related risk of severe joint problems for even modest symptom improvement. CONCLUSION: A pharmaceutical treatment with a risk of severe joint problems was viewed as an acceptable alternative to other treatments with comparable efficacy but risks associated with NSAIDs or opioids.

Baseline self-report 'central mechanisms' trait predicts persistent knee pain in the Knee Pain in the Community (KPIC) cohort.

OBJECTIVES: We investigated whether baseline scores for a self-report trait linked to central mechanisms predict 1 year pain outcomes in the Knee Pain in the Community cohort. METHOD: 1471 participants reported knee pain at baseline and responded to a 1-year follow-up questionnaire, of whom 204 underwent pressure pain detection thresholds (PPTs) and radiographic assessment at baseline. Logistic and linear regression models estimated the relative risks (RRs) and associations (ß) between self-report traits, PPTs and pain outcomes. Discriminative performance for each predictor was compared using receiver-operator characteristics (ROC) curves. RESULTS: Baseline Central Mechanisms trait scores predicted pain persistence (Relative Risk, RR = 2.10, P = 0.001) and persistent pain severity (ß = 0.47, P < 0.001), even after adjustment for age, sex, BMI, radiographic scores and symptom duration. Baseline joint-line PPTs also associated with pain persistence (RR range = 0.65 to 0.68, P < 0.02), but only in univariate models. Lower baseline medial joint-line PPT was associated with persistent pain severity (ß = -0.29, P = 0.013) in a fully adjusted model. The Central Mechanisms trait model showed good discrimination of pain persistence cases from resolved pain cases (Area Under the Curve, AUC = 0.70). The discrimination power of other predictors (PPTs (AUC range = 0.51 to 0.59), radiographic OA (AUC = 0.62), age, sex and BMI (AUC range = 0.51 to 0.64), improved significantly (P < 0.05) when the central mechanisms trait was included in each logistic regression model (AUC range = 0.69 to 0.74). CONCLUSION: A simple summary self-report Central Mechanisms trait score may indicate a contribution of central mechanisms to poor knee pain prognosis.

Thresholds of ultrasound synovial abnormalities for knee osteoarthritis - a cross sectional study in the general population.

OBJECTIVE: To establish "normal" ranges for synovial thickness and effusion detected by ultrasound (US) and to determine cut-offs associated with knee pain (KP) and radiographic knee osteoarthritis (RKOA) in the community. METHODS: 147 women and 152 men ≥40 years old were randomly selected from the Nottingham KP and Related Health in the Community (KPIC) cohort (n = 9506). The "normal" range was established using the percentile method in 163 participants who had no KP and no RKOA. Optimal (maximum sensitivity and specificity) and high specificity (90%) cut-offs were established using receiver operating characteristic (ROC) curve analysis in a comparison between people with both KP and RKOA and normal controls. RESULTS: Effusion and synovial hypertrophy differed by gender but not by age or laterality, therefore gender-specific reference limits were estimated. However, the "normal" ranges between men and women were similar for effusion (0-10.3 mm vs 0-9.8 mm), but different for synovial hypertrophy (0-6.8 mm vs 0-5.4 mm). Power Doppler Signal (PDS) in the healthy controls was uncommon (1.2% in men and 0.0% in women). The optimal cut-off was 7.4 mm for men and 5.3 mm for women for effusion, and 3.7 and 1.6 for hypertrophy respectively. The high specificity cut-off was 8.9 for men and 7.8 for women for effusion, and 5.8 and 4.2 for hypertrophy respectively. CONCLUSIONS: US effusion and synovial hypertrophy but not PDS are common, but differ by gender, in community-derived people without painful knee OA. Currently used cut-offs for abnormality need reappraisal.