Memory, mood and associated neuroanatomy in individuals with steroid sulphatase deficiency (X-linked ichthyosis).

Steroid sulphatase (STS) cleaves sulphate groups from steroid hormones, and steroid (sulphate) levels correlate with mood and age-related cognitive decline. In animals, STS inhibition or deletion of the associated gene, enhances memory/neuroprotection and alters hippocampal neurochemistry. Little is known about the consequences of constitutive STS deficiency on memory-related processes in humans. We investigated self-reported memory performance (Multifactorial Memory Questionnaire), word-picture recall and recent mood (Kessler Psychological Distress Scale, K10) in adult males with STS deficiency diagnosed with the dermatological condition X-linked ichthyosis (XLI; n = 41) and in adult female carriers of XLI-associated genetic variants (n = 79); we compared results to those obtained from matched control subjects [diagnosed with ichthyosis vulgaris (IV, n = 98) or recruited from the general population (n = 250)]. Using the UK Biobank, we compared mood/memory-related neuroanatomy in carriers of genetic deletions encompassing STS (n = 28) and non-carriers (n = 34,522). We found poorer word-picture recall and lower perceived memory abilities in males with XLI and female carriers compared with control groups. XLI-associated variant carriers and individuals with IV reported more adverse mood symptoms, reduced memory contentment and greater use of memory aids, compared with general population controls. Mood and memory findings appeared largely independent. Neuroanatomical analysis only indicated a nominally-significantly larger molecular layer in the right hippocampal body of deletion carriers relative to non-carriers. In humans, constitutive STS deficiency appears associated with mood-independent impairments in memory but not with large effects on underlying brain structure; the mediating psychobiological mechanisms might be explored further in individuals with XLI and in new mammalian models lacking STS developmentally.

Cardiac arrhythmia in individuals with steroid sulfatase deficiency (X-linked ichthyosis): candidate anatomical and biochemical pathways.

Circulating steroids, including sex hormones, can affect cardiac development and function. In mammals, steroid sulfatase (STS) is the enzyme solely responsible for cleaving sulfate groups from various steroid molecules, thereby altering their activity and water solubility. Recent studies have indicated that Xp22.31 genetic deletions encompassing STS (associated with the rare dermatological condition X-linked ichthyosis), and common variants within the STS gene, are associated with a markedly elevated risk of cardiac arrhythmias, notably atrial fibrillation/flutter. Here, we consider emerging basic science and clinical findings which implicate structural heart abnormalities (notably septal defects) as a mediator of this heightened risk, and propose candidate cellular and biochemical mechanisms. Finally, we consider how the biological link between STS activity and heart structure/function might be investigated further and the clinical implications of work in this area.

Specific T-cell subsets have a role in anti-viral immunity and pathogenesis but not viral dynamics or onwards vector transmission of an important livestock arbovirus.

Introduction: Bluetongue virus (BTV) is an arthropod-borne Orbivirus that is almost solely transmitted by Culicoides biting midges and causes a globally important haemorrhagic disease, bluetongue (BT), in susceptible ruminants. Infection with BTV is characterised by immunosuppression and substantial lymphopenia at peak viraemia in the host. Methods: In this study, the role of cell-mediated immunity and specific T-cell subsets in BTV pathogenesis, clinical outcome, viral dynamics, immune protection, and onwards transmission to a susceptible Culicoides vector is defined in unprecedented detail for the first time, using an in vivo arboviral infection model system that closely mirrors natural infection and transmission of BTV. Individual circulating CD4+, CD8+, or WC1+ γδ T-cell subsets in sheep were depleted through the administration of specific monoclonal antibodies. Results: The absence of cytotoxic CD8+ T cells was consistently associated with less severe clinical signs of BT, whilst the absence of CD4+ and WC1+ γδ T cells both resulted in an increased clinical severity. The absence of CD4+ T cells also impaired both a timely protective neutralising antibody response and the production of IgG antibodies targeting BTV non-structural protein, NS2, highlighting that the CD4+ T-cell subset is important for a timely protective immune response. T cells did not influence viral replication characteristics, including onset/dynamics of viraemia, shedding, or onwards transmission of BTV to Culicoides. We also highlight differences in T-cell dependency for the generation of immunoglobulin subclasses targeting BTV NS2 and the structural protein, VP7. Discussion: This study identifies a diverse repertoire of T-cell functions during BTV infection in sheep, particularly in inducing specific anti-viral immune responses and disease manifestation, and will support more effective vaccination strategies.

Menopause age, reproductive span and hormone therapy duration predict the volume of medial temporal lobe brain structures in postmenopausal women.

Medial temporal lobe (MTL) atrophy is correlated with risk and severity of Alzheimer disease (AD) pathology and cognitive decline. Increasing evidence suggest that oestrogens affect the aging of MTL structures. Here we investigate the relationship between reproductive hormone exposure, polygenic scores for AD risk and oestradiol concentration, MTL anatomy and cognitive performance in postmenopausal women. To this end, we used data from 10,924 female participants in the UK Biobank from whom brain MRI and genetic data were available. We fitted linear regression models to test whether the volume of structures comprising the MTL were predicted by a) timing related to menopause, b) the use and timing of hormone replacement therapy (HRT) and c) polygenic scores for AD risk and oestradiol concentration. Results showed that longer use of HRT was associated with larger parahippocampal volumes (2.53 mm3/year, p = 0.042). A later age of natural menopause, and a longer reproductive span, was associated with larger hippocampal (6.08 and 5.72 mm3/year, p = 0.0006 and 0.0005), parahippocampal (4.17 mm3 and 4.19 mm3/year, p = 0.00006 and 0.00001), amygdala (2.10 and 2.22 mm3/year, p = 0.028 and 0.01) and perirhinal cortical (2.56 and 2.95 mm3/year, p = 0.028 and 0.008) volumes. Superior prospective memory performance was associated with later age at natural menopause, and a longer reproductive span (ß = 0.05 and 0.05 respectively, p = 0.019 and 0.019). Polygenic scores for AD risk and for oestradiol concentration were not associated with MTL volume and did not interact with menopause-related factors to affect MTL structure. Our results suggest that HRT use did not have any detrimental effects on cognition or brain structure, whilst greater exposure to reproductive hormones across time is associated both with slightly larger volumes of specific MTL structures and marginally superior memory performance, independent of genetic risk for AD and genetic predisposition for higher oestradiol levels. However, the clinical utility of maintenance of oestrogens post-menopause for brain health and protection against cognitive decline is curtailed by the small effect sizes observed.

Residual Deficits in Reactive Strength After Anterior Cruciate Ligament Reconstruction in Soccer Players.

CONTEXT: Deficits in plyometric abilities are common after anterior cruciate ligament reconstruction (ACLR). Vertical rebound tasks may provide a targeted evaluation of knee function. OBJECTIVE: To examine the utility of a vertical hop test for assessing function after ACLR and establishing factors associated with performance. DESIGN: Cross-sectional study. SETTING: Rehabilitation program. PATIENTS OR OTHER PARTICIPANTS: Soccer players with a history of ACLR (n = 73) and matched control individuals (n = 195). MAIN OUTCOME MEASURE(S): The 10-second vertical hop test provided measures of jump height, the Reactive Strength Index (RSI), and asymmetry. We also examined possible predictors of hop performance, including single-legged vertical drop jump, isokinetic knee-extension strength, and the International Knee Documentation Committee questionnaire score. RESULTS: Between-limbs differences were identified only for the ACLR group, and asymmetry scores increased in those with a history of ACLR (P < .001) compared with the control group. The single-legged vertical drop jump, RSI, and knee-extension torque were significant predictors of 10-second hop height (R2 = 20.1%) and RSI (R2 = 47.1%). CONCLUSIONS: Vertical hop deficits were present after ACLR, even after participants completed a comprehensive rehabilitation program. This may have been due to reduced knee-extension and reactive strength. Vertical hop tests warrant inclusion as part of the return-to-sport test battery.

Eco-physiology and environmental impacts of newly developed rice genotypes for improved yield and nitrogen use efficiency coordinately.

Significant advancements have been made in understanding the genetic regulation of nitrogen use efficiency (NUE) and identifying crucial NUE genes in rice. However, the development of rice genotypes that simultaneously exhibit high yield and NUE has lagged behind these theoretical advancements. The grain yield, NUE, and greenhouse gas (GHG) emissions of newly-bred rice genotypes under reduced nitrogen application remain largely unknown. To address this knowledge gap, field experiments were conducted, involving 80 indica (14 to 19 rice genotypes each year in Wuxue, Hubei) and 12 japonica (8 to 12 rice genotypes each year in Yangzhou, Jiangsu). Yield, NUE, agronomy, and soil parameters were assessed, and climate data were recorded. The experiments aimed to assess genotypic variations in yield and NUE among these genotypes and to investigate the eco-physiological basis and environmental impacts of coordinating high yield and high NUE. The results showed significant variations in yield and NUE among the genotypes, with 47 genotypes classified as moderate-high yield with high NUE (MHY_HNUE). These genotypes demonstrated the higher yields and NUE levels, with 9.6 t ha-1, 54.4 kg kg-1, 108.1 kg kg-1, and 64 % for yield, NUE for grain and biomass production, and N harvest index, respectively. Nitrogen uptake and tissue concentration were key drivers of the relationship between yield and NUE, particularly N uptake at heading and N concentrations in both straw and grain at maturity. Increase in pre-anthesis temperature consistently lowered yield and NUE. Genotypes within the MHY_HNUE group exhibited higher methane emissions but lower nitrous oxide emissions compared to those in the low to middle yield and NUE group, resulting in a 12.8 % reduction in the yield-scaled greenhouse gas balance. In conclusion, prioritizing crop breeding efforts on yield and resource use efficiency, as well as developing genotypes resilient to high temperatures with lower GHGs, can mitigate planetary warming.

Characterising heart rhythm abnormalities associated with Xp22.31 deletion.

BACKGROUND: Genetic deletions at Xp22.31 are associated with the skin condition X linked ichthyosis (XLI), and with a substantially increased risk of atrial fibrillation/flutter (AF), in males. AF is associated with elevated thrombosis, heart failure, stroke and dementia risk. METHODS: Through: (a) examining deletion carriers with a diagnosis of AF in UK Biobank, (b) undertaking an online survey regarding abnormal heart rhythms (AHRs) in men/boys with XLI and female carriers of XLI-associated deletions and (c) screening for association between common genetic variants within Xp22.31 and idiopathic AF-related conditions in UK Biobank, we have investigated how AHRs manifest in deletion carriers, and have identified associated risk factors/comorbidities and candidate gene(s). Finally, we examined attitudes towards heart screening in deletion carriers. RESULTS: We show that AHRs may affect up to 35% of deletion carriers (compared with <20% of age-matched non-carriers), show no consistent pattern of onset but may be precipitated by stress, and typically resolve quickly and respond well to intervention. Gastrointestinal (GI) conditions and asthma/anaemia were the most strongly associated comorbidities in male and female deletion carriers with AHR, respectively. Genetic analysis indicated significant enrichment of common AF risk variants around STS (7 065 298-7 272 682 bp in GRCh37/hg19 genome build) in males, and of common GI disorder and asthma/anaemia risk variants around PNPLA4 (7 866 804-7 895 780 bp) in males and females, respectively. Deletion carriers were overwhelmingly in favour of cardiac screening implementation. CONCLUSION: Our data suggest AHRs are frequently associated with Xp22.31 deletion, and highlight subgroups of deletion carriers that may be prioritised for screening. Examining cardiac function further in deletion carriers, and in model systems lacking steroid sulfatase, may clarify AF pathophysiology.

X-linked ichthyosis: New insights into a multi-system disorder.

Background: X-linked ichthyosis (XLI) is a rare genetic condition almostexclusively affecting males; it is characterised by abnormal desquamation and retentionhyperkeratosis, and presents with polygonal brown scales. Most cases resultfrom genetic deletions within Xp22.31 spanning the STS (steroid sulfatase)gene, with the remaining cases resulting from STS-specific mutations. For manyyears it has been recognised that individuals with XLI are at increased risk ofcryptorchidism and corneal opacities. Methods: We discuss emerging evidence that such individuals are alsomore likely to be affected by a range of neurodevelopmental and psychiatrictraits, by cardiac arrhythmias, and by rare fibrotic and bleeding-relatedconditions. We consider candidate mechanisms that may confer elevatedlikelihood of these individual conditions, and propose a novel commonbiological risk pathway. Results: Understanding the prevalence, nature and co-occurrence ofcomorbidities associated with XLI is critical for ensuring early identificationof symptoms and for providing the most effective genetic counselling andmultidisciplinary care for affected individuals. Conclusion: Future work in males with XLI, and in new preclinical andcellular model systems, should further clarify underlying pathophysiologicalmechanisms amenable to therapeutic intervention.

Sustainable production of healthy, affordable food in the UK: The pros and cons of plasticulture.

An evolving green agenda as the UK seeks to achieve 'net zero' in greenhouse gas emissions by 2050, coupled with our new trading relationship with the European Union, is resulting in new government policies, which will be disruptive to Britain's traditional food and farming practices. These policies encourage sustainable farming and land-sparing to restore natural habitats and will provide an opportunity to address issues such as high emissions of GHGs and dwindling biodiversity resulting from many intensive agricultural practices. To address these and other food challenges such as global conflicts and health issues, Britain will need a revolution in its food system. The aim of this paper is to make the case for such a food revolution where additional healthy food for the UK population is produced in-country in specialised production units for fruits and vegetables developed on sites previously considered unsuitable for crop production. High crop productivity can be achieved in low-cost controlled environments, making extensive use of novel crop science and modern controlled-environment technology. Such systems must be operated with very limited environmental impact. In recent years, growth in the application of plasticulture in UK horticulture has driven some increases in crop yield, quality and value. However, the environmental cost of plastic production and plastic pollution is regarded as a generational challenge that faces the earth system complex. The distribution of plastic waste is ubiquitous, with a significant pollution load arising from a range of agricultural practices. The primary receptor of agriplastic pollution is agricultural soil. Impacts of microplastics on crop productivity and quality and also on human health are only now being investigated. This paper explores the possibility that we can mitigate the adverse environmental effects of agriplastics and thereby exploit the potential of plasticulture to enhance the productivity and positive health impact of UK horticulture.

Digitally enabled cardiac rehabilitation following coronary revascularization: results from a single centre feasibility study.

Wearable activity monitors, together with smartphone-based health and fitness applications (apps), are becoming more accessible and their widespread use provides an additional opportunity for the recording of cardiovascular metrics in patients with cardiovascular disease. The use of selected metrics by cardiac rehabilitation (CR) programmes allows the facilitation of individualized and tailored positive lifestyle changes to patients and places the patient at the centre of their recovery programme. To investigate the role of such devices on outcomes with patients on a CR programme, a cohort/case-control study was conducted. Patients post-myocardial infarction who were treated with either percutaneous coronary intervention or surgical coronary revascularisation at a single centre were invited to use a physical activity monitor linked to a customized app at their initial assessment for the rehabilitation programme. Those who accepted were allocated to the treatment group. The control group was selected from a larger pool of 400 historical and concurrent patients. Propensity matching was used to associate each case with their closest control. The changes in self-reported physical activity were similar for both groups at the end of the CR programme (EOP). The digitally monitored group tended to achieve greater METS (metabolic equivalent of task - a measure of exercise intensity) at 12 weeks (P < 0.059); however, no difference was observed in the overall change in METS at EOP (P < 0.333). Although no difference was noted in diastolic blood pressure, a statistically significant drop in the systolic blood pressure in the digitally monitored group (P < 0.004) was detected. In this study, the innovative combination of technology and face-to-face CR showed promising results and assisted the individualization of delivered content. This intervention could easily be replicated and expanded. Challenges are the recruitment of the elderly population, those who may be less engaged with or have less access to technology, and the underrepresentation of women in the study sample.

Stronger Subjects Select a Movement Pattern That May Reduce Anterior Cruciate Ligament Loading During Cutting.

ABSTRACT: Davies, WT, Ryu, JH, Graham-Smith, P, Goodwin, JE, and Cleather, DJ. Stronger subjects select a movement pattern that may reduce anterior cruciate ligament loading during cutting. J Strength Cond Res 36(7): 1853-1859, 2022-Increased strength has been suggested to reduce the incidence of anterior cruciate ligament (ACL) injury as part of wider neuromuscular training programs; however, the mechanism of this is not clear. Cutting is a high-risk maneuver for ACL injury, but limited research exists as to how strength affects sagittal plane biomechanics during this movement. Sixteen subjects were split into a stronger and weaker group based on their relative peak isometric strength in a unilateral squat (stronger: 29.0 ± 3.4 N·kg-1 and weaker: 18.3 ± 4.1 N·kg-1). Subjects performed 45° cuts with maximal intent 3 times, at 3 different approach velocities (2, 4, and 6 m·s-1). Kinematics and ground reaction forces were collected using optical motion capture and a force platform. The stronger group had lower knee extensor moments, larger hip extensor moments, and a greater peak knee flexion angle than the weaker group (p < 0.05). There was a trend for greater knee flexion at initial contact in the stronger group. There were no differences in resultant ground reaction forces between groups. The stronger group relied more on the hip than the knee during cutting and reached greater knee flexion angles. This could decrease ACL loading by reducing the extensor moment required at the knee during weight acceptance. Similarly, the greater knee flexion angle during weight acceptance is likely to be protective of the ACL.

Mood symptoms, neurodevelopmental traits, and their contributory factors in X-linked ichthyosis, ichthyosis vulgaris and psoriasis.

BACKGROUND: High rates of adverse mood/neurodevelopmental traits are seen in multiple dermatological conditions, and can significantly affect patient quality of life. Understanding the sex-specific nature, magnitude, impact and basis of such traits in lesser-studied conditions like ichthyosis, is important for developing effective interventions. AIM: To quantify and compare relevant psychological traits in men with X-linked ichthyosis (XLI, n = 54) or in XLI carrier women (n = 83) and in patients with ichthyosis vulgaris (IV, men n = 23, women n = 59) or psoriasis (men n = 30, women n = 122), and to identify factors self-reported to contribute most towards depressive, anxious and irritable phenotypes. METHODS: Participants recruited via relevant charities or social media completed an online survey of established questionnaires. Data were analysed by sex and skin condition, and compared with general population data. RESULTS: Compared with the general population, there was a higher rate of lifetime prevalence of mood disorder diagnoses across all groups and of neurodevelopmental disorder diagnoses in the XLI groups. The groups exhibited similarly significant elevations in recent mood symptoms (Cohen d statistic 0.95-1.28, P < 0.001) and neurodevelopmental traits (d = 0.31-0.91, P < 0.05) compared with general population controls, and self-reported moderate effects on quality of life and stigmatization. There were strong positive associations between neurodevelopmental traits and recent mood symptoms (r > 0.47, P < 0.01), and between feelings of stigmatization and quality of life, particularly in men. Numerous factors were identified as contributing significantly to mood symptoms in a condition or sex-specific, or condition or sex-independent, manner. CONCLUSION: We found that individuals with XLI, IV or psoriasis show higher levels of mood disorder diagnoses and symptoms than matched general population controls, and that the prevalence and severity of these is similar across conditions. We also identified a number of factors potentially conferring either general or condition-specific risk of adverse mood symptoms in the three skin conditions, which could be targeted clinically and/or through education programmes. In clinical practice, recognizing mood/neurodevelopmental problems in ichthyosis and psoriasis, and addressing the predisposing factors identified by this study should benefit the mental health of affected individuals.

Sex-linked genetic mechanisms and atrial fibrillation risk.

Atrial fibrillation (AF) is a cardiac condition characterised by an irregular heartbeat, atrial pathology and an elevated downstream risk of thrombosis and heart failure, as well as neurological sequelae including stroke and dementia. The prevalence and presentation of, risk factors for, and therapeutic responses to, AF differ by sex, and this sex bias may be partially explained in terms of genetics. Here, we consider four sex-linked genetic mechanisms that may influence sex-biased phenotypes related to AF and provide examples of each: X-linked gene dosage, X-linked genomic imprinting, sex-biased autosomal gene expression, and male-limited Y-linked gene expression. We highlight novel candidate risk genes and pathways that warrant further investigation in clinical and preclinical studies. Understanding the biological basis of sex differences in AF should allow better prediction of disease risk, identification of novel risk/protective factors, and the development of more effective sex-tailored interventions.

The contribution of Xp22.31 gene dosage to Turner and Klinefelter syndromes and sex-biased phenotypes.

Turner syndrome (TS) is a rare developmental condition in females caused by complete, or partial, loss of the second sex chromosome; it is associated with a number of phenotypes including short stature, ovarian failure and infertility, as well as neurobehavioural and cognitive manifestations. In contrast, Klinefelter syndrome (KS) arises from an excess of X chromosome material in males (typical karyotype is 47,XXY); like TS, KS is associated with infertility and hormonal imbalance, and behavioural/neurocognitive differences from gonadal sex-matched counterparts. Lower dosage of genes that escape X-inactivation may partially explain TS phenotypes, whilst overdosage of these genes may contribute towards KS-related symptoms. Here, I discuss new findings from individuals with deletions or duplications limited to Xp22.31 (a region escaping X-inactivation), and consider the extent to which altered gene dosage within this small interval (and of the steroid sulfatase (STS) gene in particular) may influence the phenotypic profiles of TS and KS. The expression of X-escapees can be higher in female than male tissues; I conclude by considering how lower Xp22.31 gene dosage in males may increase their likelihood of exhibiting particular phenotypes relative to females. Understanding the genetic contribution to specific phenotypes in rare disorders such as TS and KS, and to more common sex-biased phenotypes, will be important for developing more effective, and more personalised, therapeutic approaches.

A new molecular risk pathway for postpartum mood disorders: clues from steroid sulfatase-deficient individuals.

Postpartum mood disorders develop shortly after childbirth in a significant proportion of women. These conditions are associated with a range of symptoms including abnormally high or low mood, irritability, cognitive disorganisation, disrupted sleep, hallucinations/delusions, and occasionally suicidal or infanticidal ideation; if not treated promptly, they can substantially impact upon the mother's health, mother-infant bonding, and family dynamics. The biological precipitants of such disorders remain unclear, although large changes in maternal immune and hormonal physiology following childbirth are likely to play a role. Pharmacological therapies for postpartum mood disorders can be effective, but may be associated with side effects, concerns relating to breastfeeding, and teratogenicity risks when used prophylactically. Furthermore, most of the drugs that are used to treat postpartum mood disorders are the same ones that are used to treat mood episodes during non-postpartum periods. A better understanding of the biological factors predisposing to postpartum mood disorders would allow for rational drug development, and the identification of predictive biomarkers to ensure that 'at risk' mothers receive earlier and more effective clinical management. We describe new findings relating to the role of the enzyme steroid sulfatase in maternal postpartum behavioural processes, and discuss how these point to a novel molecular risk pathway underlying postpartum mood disorders. Specifically, we suggest that aberrant steroid hormone-dependent regulation of neuronal calcium influx via extracellular matrix proteins and membrane receptors involved in responding to the cell's microenvironment might be important. Testing of this hypothesis might identify novel therapeutic targets and predictive biomarkers.

A fatal case of infective endocarditis complicated by acute COVID-19 pneumonia.

A 74-year-old man with no co-morbidities presented to hospital with a 3-day history of diarrhoea and vomiting. He met the modified Duke's criteria for definite infective endocarditis and was immediately started on an intravenous antibiotic. Over Days 1-9, he developed renal failure. On Day 10, he was transferred to a tertiary hospital for mitral valve replacement. However, he tested positive for SARS-CoV-2 on arrival at the tertiary hospital, which delayed his surgery. He underwent bi-weekly nasopharyngeal swabs for SARS-CoV-2 with a plan to operate as soon as he tested negative, or as soon as his incubation period for COVID-19 pneumonia had elapsed. Unfortunately, he died on Day 31 from acute respiratory distress syndrome secondary to COVID-19 pneumonia. We describe the challenges in deciding on the optimal timing for valve replacement. We conclude by suggesting that earlier valve replacement may result in better outcomes.

Investigating the Effects of Cuing Medication Availability on Patient-controlled Analgesia Pump Usage in Pediatric Patients: Results of a Randomized Controlled Trial.

OBJECTIVES: The study of patient-controlled analgesia (PCA) behaviors has led to a greater understanding of factors that affect the pain experience. Although PCA behaviors can be influenced by cues to medication availability, no studies have examined the effects of such cues in pediatric populations. MATERIALS AND METHODS: This randomized controlled trial examined patient satisfaction with pain management, PCA behaviors, opioid consumption, and state anxiety in a sample of 125 postsurgical children and adolescents (7 to 17 y). Patients were randomized to a "light" group (lockout period status cued by light on the PCA button) or control group (no cues to medication availability). RESULTS: Although cuing did not affect patient satisfaction with pain management (P=0.11), patients in the light group consumed significantly more opioid than those in the control group (adj. P=0.016). This effect was primarily because of children in the light group (median, 0.019; interquartile range, 0.012 to 0.036 mg/kg/h) consuming more opioid than children (12 y or younger) in control group (median, 0.015; interquartile range, 0.006 to 0.025 mg/kg/h) (P=0.007). In contrast to the control group, for patients in the light group, opioid consumption was unrelated to pain and the proportion of patients with a 1:1 injections:attempts ratio was higher (P<0.001) across the study period. DISCUSSION: The overall pattern of results suggests that patients in the light group used their PCA in response to the light more than in response to their pain, which likely reflects operant influences on PCA behavior by pediatric patients.

Heart Failure Drug Modifies the Intrinsic Dynamics of the Pre-Power Stroke State of Cardiac Myosin.

Omecamtiv mecarbil (OM), currently investigated for the treatment of heart failure, is the first example of a new class of drugs (cardiac myotropes) that can modify muscle contractility by directly targeting sarcomeric proteins. Using atomistic molecular dynamics simulations, we show that the binding of OM to the pre-power stroke state of cardiac myosin inhibits the functional motions of the protein and potentially affects Pi release from the nucleotide binding site. We also show that the changes in myosin ATPase activity induced by a set of OM analogues can be predicted from their relative affinity to the pre-power stroke state compared to the near rigor one, indicating that conformational selectivity plays an important role in determining the activity of these compounds.

Residual deficits in reactive strength indicate incomplete restoration of athletic qualities following anterior cruciate ligament reconstruction in professional soccer players.

CONTEXT: Deficits in plyometric abilities are common following anterior cruciate ligament reconstruction (ACLR). Vertical rebound tasks may provide a targeted evaluation of knee function. OBJECTIVE: Examine the utility of a vertical hop test to assess function following ACLR and establish factors associated with performance. DESIGN: Cross-sectional Setting: Rehabilitation Participants: Soccer players with a history of ACLR (N = 73) and matched controls (N = 195) Main outcome measures: 10 second vertical hop test including measures of jump height, reactive strength index (RSI) and asymmetry. We also examined possible predictors of hop performance including single leg vertical drop jump (SLDVJ), isokinetic knee extension strength, and the international knee documentation committee questionnaire. RESULTS: Significant between-limb differences were identified for the ACLR group only and asymmetry scores increased in those with a history of ACLR (P < 0.001) compared to controls. SLDVJ RSI and knee extension torque were significant predictors of 10 second hop height (R2 = 20.1%) and RSI (R2 = 47.1%). CONCLUSIONS: Vertical hop deficits are present following ACLR even after completing a comprehensive rehabilitation program. This may be due to reduced knee extension and reactive strength. Vertical hop tests warrant inclusion as part of return to sport test battery.