Humeral torsion and activity-related change in the human upper limb and pectoral girdle. A biomechanical investigation and social implications.

This project investigas humeral torsion and activity-related change in the human upper limb. Increased humeral torsion angles have been identified in the professional throwing athlete and may be associated with strenuous activity. The nature of humeral torsion as an osteogenic response to the strain environment is investigated to identify its role in the behavioural morphology of the upper limb. These physical manifestations of strenuous physical activity provide an insight into the make-up of medieval armies prior to the establishment of standing armies. Populations analysed include two blade-injured samples, Towton and a subsample of blade-injured men from the Priory of St. Andrew, Fishergate, York. The men from the Mary Rose, a Tudor warship are also investigated. Other samples analysed include the rural sites of Wharram Percy and Hickleton, the urban cemeteries from the Priory of St. Andrew, Fishergate,York and the leprosarium of Sts. James and Mary Magdalene, Chichester, the modern cadaver-based Terry collection and non-human primates, Gorilla sp., Pan sp., Pongo sp., and Macaca sp.. Measurement of the humeral torsion angle and external measurements and indices of architecture, articulations and robusticity are employed. Cross-sectional geometric properties are investigated using CT imaging of the paired humeri from a sub-sample of blade-injured individuals and a comparative sample of those who were not. Bilateral asymmetry is investigated to identify the role of plasticity within the humerus and to reveal aspects of limb dominance. The results are compared with non-human primate species to obtain insight into inter-species differences. Results indicate the humeral torsion is not ontogenetically constrained, but is highly variable between and within populations, individuals and even between sides. Biomechanical analyses indicate that in the Towton population, humeral torsion may serve as part of a two-stage adaptation, in which the architecture is modified to enable greater biomechanical efficiency in distributing strain, reducing the need of increased cortical thickness. Changes in humeral torsion related to strenuous activity have been identified, although in the blade-injured samples it is decreased torsion angles, w hile in the comparative sample it is increased torsion angles that significantly correlate with limb hypertrophy. Humeral torsion appears to be influenced by other measurementd of humeral architecture, specifically, the amount of anterior bowing and anterior curvature to the distal humeral shaft. This work demonstrates the need for individual rather than population-based analyses, as the heterogeneity within population samples obscures individual variation in activity patterns. This analysis provides baseline data for typical populations of the Middle Ages. From this, it is then possible to investigate the individual within this baseline, to identify those who stand out from their samples through habitual, strenuous activity patterns. Movement patterns identified related to warfare include those consistent with the use of the longbow in the Towton sample and the use of a sword in the Fishergate blade-injured sample. These men, and those of the Mary Rose, appear to have either been selected for combat based on size, or benefited from a more nutritious diet during growth.Arts and Humanities Research Board (AHRB), Francis Raymond Hudson Fund, Andy Jagger Fund

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Activity-Related Skeletal Change in Medieval Humeri: Cross-Sectional and Architectural Alterations.

NoThis paper examines humeral cross-sectional properties in two different samples of later medieval date: a group of blade-injured males from the sites of Towton, North Yorkshire, and Fishergate in the City of York, England, and a comparative group of nonblade-injured males also from the site of Fishergate in York. CT image slices were taken of the humeral shaft at 20%, 35%, 50%, 65%, and 80% from the distal end to investigate population differences in levels and patterns of mechanical loading. Bilateral asymmetry is investigated and comparisons are made with different populations of varying activity levels. Architectural changes such as humeral torsion are also investigated to determine the relationship between architectural changes and biomechanical efficiency. Results show significant differences in diaphyseal robusticity between the Towton sample and the comparative population, as well as significant differences in diaphyseal shape both between limbs within the Towton sample and between blade-injured samples. Population differences were also identified in the level of bilateral asymmetry, further demonstrating the differences in movement and activity patterns both between and within samples. These variations may relate to distinctive, more strenuous weapon use and differences in strenuous movement patterns in the two groups

Humeral torsion and activity-related change in the human upper limb and pectoral girdle : a biomechanical investigation and social implications

This project investigas humeral torsion and activity-related change in the human upper limb. Increased humeral torsion angles have been identified in the professional throwing athlete and may be associated with strenuous activity. The nature of humeral torsion as an osteogenic response to the strain environment is investigated to identify its role in the behavioural morphology of the upper limb. These physical manifestations of strenuous physical activity provide an insight into the make-up of medieval armies prior to the establishment of standing armies. Populations analysed include two blade-injured samples, Towton and a subsample of blade-injured men from the Priory of St. Andrew, Fishergate, York. The men from the Mary Rose, a Tudor warship are also investigated. Other samples analysed include the rural sites of Wharram Percy and Hickleton, the urban cemeteries from the Priory of St. Andrew, Fishergate,York and the leprosarium of Sts. James and Mary Magdalene, Chichester, the modern cadaver-based Terry collection and non-human primates, Gorilla sp., Pan sp., Pongo sp., and Macaca sp.. Measurement of the humeral torsion angle and external measurements and indices of architecture, articulations and robusticity are employed. Cross-sectional geometric properties are investigated using CT imaging of the paired humeri from a sub-sample of blade-injured individuals and a comparative sample of those who were not. Bilateral asymmetry is investigated to identify the role of plasticity within the humerus and to reveal aspects of limb dominance. The results are compared with non-human primate species to obtain insight into inter-species differences. Results indicate the humeral torsion is not ontogenetically constrained, but is highly variable between and within populations, individuals and even between sides. Biomechanical analyses indicate that in the Towton population, humeral torsion may serve as part of a two-stage adaptation, in which the architecture is modified to enable greater biomechanical efficiency in distributing strain, reducing the need of increased cortical thickness. Changes in humeral torsion related to strenuous activity have been identified, although in the blade-injured samples it is decreased torsion angles, w hile in the comparative sample it is increased torsion angles that significantly correlate with limb hypertrophy. Humeral torsion appears to be influenced by other measurementd of humeral architecture, specifically, the amount of anterior bowing and anterior curvature to the distal humeral shaft. This work demonstrates the need for individual rather than population-based analyses, as the heterogeneity within population samples obscures individual variation in activity patterns. This analysis provides baseline data for typical populations of the Middle Ages. From this, it is then possible to investigate the individual within this baseline, to identify those who stand out from their samples through habitual, strenuous activity patterns. Movement patterns identified related to warfare include those consistent with the use of the longbow in the Towton sample and the use of a sword in the Fishergate blade-injured sample. These men, and those of the Mary Rose, appear to have either been selected for combat based on size, or benefited from a more nutritious diet during growth.EThOS - Electronic Theses Online ServiceArts and Humanities Research Board (AHRB), Francis Raymond Hudson Fund, Andy Jagger Fund.GBUnited Kingdo

Traumatic brain injury : integrated approaches to improve prevention, clinical care, and research

Rahul Raj on työryhmän InTBIR Participants Investigators jäsen.Peer reviewe

Rare pathogenic variants in WNK3 cause X-linked intellectual disability

Purpose: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. Method: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). Results: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had ID with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. Conclusion: Pathogenic WNK3 variants cause a rare form of human X-linked ID with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.</p