Mathematical modeling of exercise fatigability in the severe domain: A unifying integrative framework in isokinetic condition.

Muscle fatigue is the decay in the ability of muscles to generate force, and results from neural and metabolic perturbations. This article presents an integrative mathematical model that describes the decrease in maximal force capacity (i.e. fatigue) over exercises performed at intensities above the critical force Fc (i.e. severe domain). The model unifies the previous Critical Power Model and All-Out Model and can be applied to any exercise described by a changing force F over time. The assumptions of the model are (i) isokinetic conditions, an intensity domain of Fc

Testing the predictive capacity of a muscle fatigue model on electrically stimulated adductor pollicis.

PURPOSE: Based on the critical power (Pc or critical force; Fc) concept, a recent mathematical model formalised the proportional link between the decrease in maximal capacities during fatiguing exercises and the amount of impulse accumulated above Fc. This study aimed to provide experimental support to this mathematical model of muscle fatigability in the severe domain through testing (i) the model identifiability using non-exhausting tests and (ii) the model ability to predict time to exhaustion (tlim) and maximal force (Fmax) decrease. METHODS: The model was tested on eight participants using electrically stimulated adductor pollicis muscle force. The Fmax was recorded every 15 s for all tests, including five constant tests to estimate the initial maximal force (Fi), Fc, and a time constant (τ). The model's parameters were used to compare the predicted and observed tlim values of the incremental ramp test and Fmax(t) of the sine test. RESULTS: The results showed that the model accurately estimated Fi, Fc, and τ (CI95% = 2.7%Fi and 9.1 s for Fc and τ, respectively; median adjusted r2 = 0.96) and predicted tlim and Fmax with low systematic and random errors (11 ± 20% and - 1.8 ± 7.7%Fi, respectively). CONCLUSION: This study revealed the potential applications of a novel mathematical formalisation that encompasses previous research on the critical power concept. The results indicated that the model's parameters can be determined from non-exhaustive tests, as long as maximal capacities are regularly assessed. With these parameters, the evolution of maximal capacities (i.e. fatigability) at any point during a known exercise and the time to exhaustion can be accurately predicted.

Neuromuscular fatigability during repeated sprints assessed with an innovative cycle ergometer.

PURPOSE: Repeated sprint ability is an integral component of team sports. This study aimed to evaluate fatigability development and its aetiology during and immediately after a cycle repeated sprint exercise performed until a given fatigability threshold. METHODS: On an innovative cycle ergometer, 16 healthy males completed an RSE (10-s sprint/28-s recovery) until task failure (TF): a 30% decrease in sprint mean power (Pmean). Isometric maximum voluntary contraction of the quadriceps (IMVC), central alterations [voluntary activation (VA)], and peripheral alterations [twitch (Pt)] were evaluated before (pre), immediately after each sprint (post), at TF and 3 min after. Sprints were expressed as a percentage of the total number of sprints to TF (TSTF). Individual data were extrapolated at 20, 40, 60, and 80% TSTF. RESULTS: Participants completed 9.7 ± 4.2 sprints before reaching a 30% decrease in Pmean. Post-sprint IMVCs were decreased from pre to 60% TSTF and then plateaued (pre: 345 ± 56 N, 60% 247 ± 55 N, TF: 233 ± 57 N, p < 0.001). Pt decreased from 20% and plateaued after 40% TSTF (p < 0.001, pre-TF = - 45 ± 13%). VA was not significantly affected by repeated sprints until 60% TSTF (pre-TF = - 6.5 ± 8.2%, p = 0.036). Unlike peripheral parameters, VA recovered within 3 min (p = 0.042). CONCLUSION: During an RSE, Pmean and IMVC decreases were first concomitant to peripheral alterations up to 40% TSTF and central alterations was only observed in the second part of the test, while peripheral alterations plateaued. The distinct recovery kinetics in central versus peripheral components of fatigability further confirm the necessity to reduce traditional delays in neuromuscular fatigue assessment post-exercise.

COVID-19-related intracranial imaging findings: a large single-centre experience.

AIM: To describe the neuroradiological changes in patients with coronavirus disease 2019 (COVID-19). MATERIALS AND METHODS: A retrospective review was undertaken of 3,403 patients who were confirmed positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and admitted to Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK between 1 March 2020 and 31 May 2020, and who underwent neuroimaging. Abnormal brain imaging was evaluated in detail and various imaging patterns on magnetic resonance imaging MRI were identified. RESULTS: Of the 3,403 patients with COVID-19, 167 (4.9%) had neurological signs or symptoms warranting neuroimaging. The most common indications were delirium (44/167, 26%), focal neurology (37/167, 22%), and altered consciousness (34/167, 20%). Neuroimaging showed abnormalities in 23% of patients, with MRI being abnormal in 20 patients and computed tomography (CT) in 18 patients. The most consistent neuroradiological finding was microhaemorrhage with a predilection for the splenium of the corpus callosum (12/20, 60%) followed by acute or subacute infarct (5/20, 25%), watershed white matter hyperintensities (4/20, 20%), and susceptibility changes on susceptibility-weighted imaging (SWI) in the superficial veins (3/20, 15%), acute haemorrhagic necrotising encephalopathy (2/20, 10%), large parenchymal haemorrhage (2/20, 10%), subarachnoid haemorrhage (1/20, 5%), hypoxic-ischaemic changes (1/20, 5%), and acute disseminated encephalomyelitis (ADEM)-like changes (1/20, 5%). CONCLUSION: Various imaging patterns on MRI were observed including acute haemorrhagic necrotising encephalopathy, white matter hyperintensities, hypoxic-ischaemic changes, ADEM-like changes, and stroke. Microhaemorrhages were the most common findings. Prolonged hypoxaemia, consumption coagulopathy, and endothelial disruption are the likely pathological drivers and reflect disease severity in this patient cohort.

From public health genomics to precision public health: a 20-year journey.

In this paper, we review the evolution of the field of public health genomics in the United States in the past two decades. Public health genomics focuses on effective and responsible translation of genomic science into population health benefits. We discuss the relationship of the field to the core public health functions and essential services, review its evidentiary foundation, and provide examples of current US public health priorities and applications. We cite examples of publications to illustrate how Genetics in Medicine reflected the evolution of the field. We also reflect on how public-health genomics is contributing to the emergence of "precision public health" with near-term opportunities offered by the US Precision Medicine (AllofUs) Initiative.

Trends in utilization and costs of BRCA testing among women aged 18-64 years in the United States, 2003-2014.

PurposeWe examined 12-year trends in BRCA testing rates and costs in the context of clinical guidelines, national policies, and other factors.MethodsWe estimated trends in BRCA testing rates and costs from 2003 to 2014 for women aged 18-64 years using private claims data and publicly reported revenues from the primary BRCA testing provider.ResultsThe percentage of women with zero out-of-pocket payments for BRCA testing increased during 2013-2014, after 7 years of general decline, coinciding with a clarification of Affordable Care Act coverage of BRCA genetic testing. Beginning in 2007, family history accounted for an increasing proportion of women with BRCA tests compared with personal history, coinciding with BRCA testing guidelines for primary care settings and direct-to-consumer advertising campaigns. During 2013-2014, BRCA testing rates based on claims grew at a faster rate than revenues, following 3 years of similar growth, consistent with increased marketplace competition. In 2013, BRCA testing rates based on claims increased 57%, compared with 11% average annual increases over the preceding 3 years, coinciding with celebrity publicity.ConclusionThe observed trends in BRCA testing rates and costs are consistent with possible effects of several factors, including the Affordable Care Act, clinical guidelines and celebrity publicity.

Foster home integration as a temporal indicator of relational well-being.

This study sought to identify factors that contribute to the relational well-being of youth in substitute care. Using data from the [BLIND] study, youth responded to a 9-item measure of positive home integration, a scale designed to assess the relational experiences of youth to their caregivers and their integration into the foster home. Data were collected from youth in six month intervals, for an 18-month period of time. Latent growth curve modeling procedures were employed to determine if child, family, and case characteristics influenced youth's home integration trajectories. Results suggest stability in youth reports of home integration over time; however, children who were older at the time of study enrollment and youth who experienced placement changes during the period of observation experienced decreased home integration during the 18-month period. Results suggest youth's perspectives of home integration may in part be a function of the child's developmental stage and their experiences with foster care placement instability. Implications for practice and future research are discussed.

Versatile variable temperature insert at the DEIMOS beamline for in situ electrical transport measurements.

The design and the first experiments are described of a versatile cryogenic insert used for its electrical transport capabilities. The insert is designed for the cryomagnet installed on the DEIMOS beamline at the SOLEIL synchrotron dedicated to magnetic characterizations through X-ray absorption spectroscopy (XAS) measurements. This development was spurred by the multifunctional properties of novel materials such as multiferroics, in which, for example, the magnetic and electrical orders are intertwined and may be probed using XAS. The insert thus enables XAS to in situ probe this interplay. The implementation of redundant wiring and careful shielding also enables studies on operating electronic devices. Measurements on magnetic tunnel junctions illustrate the potential of the equipment toward XAS studies of in operando electronic devices.

Hysteresis and change of transition temperature in thin films of Fe{[Me2Pyrz]3BH}2, a new sublimable spin-crossover molecule.

Thin films of the spin-crossover (SCO) molecule Fe{[Me2Pyrz]3BH}2 (Fe-pyrz) were sublimed on Si/SiO2 and quartz substrates, and their properties investigated by X-ray absorption and photoemission spectroscopies, optical absorption, atomic force microscopy, and superconducting quantum interference device. Contrary to the previously studied Fe(phen)2(NCS)2, the films are not smooth but granular. The thin films qualitatively retain the typical SCO properties of the powder sample (SCO, thermal hysteresis, soft X-ray induced excited spin-state trapping, and light induced excited spin-state trapping) but present intriguing variations even in micrometer-thick films: the transition temperature decreases when the thickness is decreased, and the hysteresis is affected. We explain this behavior in the light of recent studies focusing on the role of surface energy in the thermodynamics of the spin transition in nano-structures. In the high-spin state at room temperature, the films have a large optical gap (∼5 eV), decreasing at thickness below 50 nm, possibly due to film morphology.

Horizon scanning for translational genomic research beyond bench to bedside.

PURPOSE: The dizzying pace of genomic discoveries is leading to an increasing number of clinical applications. In this report, we provide a method for horizon scanning and 1 year data on translational research beyond bench to bedside to assess the validity, utility, implementation, and outcomes of such applications. METHODS: We compiled cross-sectional results of ongoing horizon scanning of translational genomic research, conducted between 16 May 2012 and 15 May 2013, based on a weekly, systematic query of PubMed. A set of 505 beyond bench to bedside articles were collected and classified, including 312 original research articles; 123 systematic and other reviews; 38 clinical guidelines, policies, and recommendations; and 32 articles describing tools, decision support, and educational materials. RESULTS: Most articles (62%) addressed a specific genomic test or other health application; almost half of these (n = 180) were related to cancer. We estimate that these publications account for 0.5% of reported human genomics and genetics research during the same time. CONCLUSION: These data provide baseline information to track the evolving knowledge base and gaps in genomic medicine. Continuous horizon scanning of the translational genomics literature is crucial for an evidence-based translation of genomics discoveries into improved health care and disease prevention.

A cancer genetics toolkit improves access to genetic services through documentation and use of the family history by primary-care clinicians.

PURPOSE: We developed, implemented, and evaluated a multicomponent cancer genetics toolkit designed to improve recognition and appropriate referral of individuals at risk for hereditary cancer syndromes. METHODS: We evaluated toolkit implementation in the women's clinics at a large Veterans Administration medical center using mixed methods, including pre-post semistructured interviews, clinician surveys, and chart reviews, and during implementation, monthly tracking of genetic consultation requests and use of a reminder in the electronic health record. We randomly sampled 10% of progress notes 6 months before (n = 139) and 18 months during implementation (n = 677). RESULTS: The toolkit increased cancer family history documentation by almost 10% (26.6% pre- and 36.3% postimplementation). The reminder was a key component of the toolkit; when used, it was associated with a twofold increase in cancer family history documentation (odds ratio = 2.09; 95% confidence interval: 1.39-3.15), and the history was more complete. Patients whose clinicians completed the reminder were twice as likely to be referred for genetic consultation (4.1-9.6%, P < 0.0001). CONCLUSION: A multicomponent approach to the systematic collection and use of family history by primary-care clinicians increased access to genetic services.

First glimpse of the soft x-ray induced excited spin-state trapping effect dynamics on spin cross-over molecules.

The dynamics of the soft x-ray induced excited spin state trapping (SOXIESST) effect of Fe(phen)2(NCS)2 (Fe-phen) powder have been investigated by x-ray absorption spectroscopy (XAS) using the total electron yield method, in a wide temperature range. The low-spin (LS) state is excited into the metastable high-spin (HS) state at a rate that depends on the intensity of the x-ray illumination it receives, and both the temperature and the intensity of the x-ray illumination will affect the maximum HS proportion that is reached. We find that the SOXIESST HS spin state transforms back to the LS state at a rate that is similar to that found for the light induced excited spin state trapping (LIESST) effect. We show that it is possible to use the SOXIESST effect in combination with the LIESST effect to investigate the influence of cooperative behavior on the dynamics of both effects. To investigate the impact of molecular cooperativity, we compare our results on Fe-phen with those obtained for Fe{[Me2Pyrz]3BH}2 (Fe-pyrz) powder, which exhibits a similar thermal transition temperature but with a hysteresis. We find that, while the time constant of the dynamic is identical for both molecules, the SOXIESST effect is less efficient at exciting the HS state in Fe-pyrz than in Fe-phen.

Does lesion type or severity predict outcome of therapy for horses with equine glandular gastric disease? - A retrospective study.

BACKGROUND: Equine glandular gastric disease (EGGD) is a common condition of the horse. Misoprostol is reported to be superior to oral omeprazole and sucralfate for treatment. Long-acting intramuscular injectable omeprazole (LAIOMEP) is a novel treatment shown to be effective in a small population. OBJECTIVES: This study aimed to determine LAIOMEP efficacy compared to misoprostol and oral omeprazole and identify characteristics that predict treatment outcome. METHODS: All horses that underwent gastroscopy between 2012 and 2019 were reviewed. Lesions were characterised by 4 blinded observers, all of whom are diplomates in equine internal medicine, using established descriptors from the ECEIM consensus statement and subjective severity. Treatment outcome was ranked as worsened, improved or healed. Consensus lesion type, lesion severity and treatment choice were compared to outcome and data screened using univariate analysis (chi-squared) to determine whether each predicted outcome. Lesion types where univariate analysis predicted a trend (p<0.2) were included in a multiple-regression analysis to identify predictors of outcome irrespective of treatment. RESULTS: Only severity significantly predicted final outcome (p = 0.025) with severe lesions being more likely to improve. Treatment choice did not significantly predict outcome. Overall healing rate was 29% (24 horses), and 43% (44 horses) improved. Treatment healing rates were 23% (10), 12% (7) and 27% (7) for LAIOMEP, misoprostol and oral omeprazole, respectively, with improvement in 69% (14), 76% (21) and 61% (9). 64% of the latter group received sucralfate. Worsening occurred in 7% (6). Treatment length varied with a median of 4 weeks (range 4-20 weeks). CONCLUSIONS: This study showed poorer therapy outcome compared to previous studies. The only initial lesion descriptor to predict outcome was severity and treatment choice did not affect outcome.

Mental health support across the sight loss pathway: a qualitative exploration of eye care patients, optometrists, and ECLOs.

BACKGROUND: The process of becoming visually impaired or blind is undoubtedly a highly emotional experience, requiring practical and psychological support. Information on mental health support provision in the UK across the sight-loss pathway, however, is largely unknown, especially amongst healthcare practitioners that are often sought after for advice: the referring optometrist and eye clinic liaison officer (ECLO). This study aims to ascertain the perceived accessibility and quality of mental health support across the sight-loss pathway. METHODS: Semi-structured individual interviews were conducted with patients with a diagnosed eye condition who had received care from a hospital eye service, referring optometrists, and ECLOs. Following interview transcription, results were synthesised in a narrative analysis. RESULTS: A total of 28 participants were included in the analysis, of which 17 were participants with various eye conditions, five were referring optometrists, and five were ECLOs. After analysis, three broad themes emerged: (1) The emotional trauma of diagnosis (2) Availability of mental health support; (3) The point where mental health support is most needed across the sight-loss pathway. Several patients reporting that they had received no offer of support nor were they signposted to any possible sources. Referring optometrists and ECLO's agreed. CONCLUSION: It is important that referring optometrists are aware of the need for mental health support services and can signpost to local support services including the third sector anytime during the referral process. Future large-scale, UK-wide research into referral practice and signposting for mental health support for patients is warranted, to identify how services can be improved in order to ensure that the wellbeing of patients is maintained.

KCTD1 is a new modulator of the KCASH family of Hedgehog suppressors.

The Sonic Hedgehog (Hh) signal transduction pathway plays a critical role in many developmental processes and, when deregulated, may contribute to several cancers, including basal cell carcinoma, medulloblastoma, colorectal, prostate, and pancreatic cancer. In recent years, several Hh inhibitors have been developed, mainly acting on the Smo receptor. However, drug resistance due to Smo mutations or non-canonical Hh pathway activation highlights the need to identify further mechanisms of Hh pathway modulation. Among these, deacetylation of the Hh transcription factor Gli1 by the histone deacetylase HDAC1 increases Hh activity. On the other end, the KCASH family of oncosuppressors binds HDAC1, leading to its ubiquitination and subsequent proteasomal degradation, leaving Gli1 acetylated and not active. It was recently demonstrated that the potassium channel containing protein KCTD15 is able to interact with KCASH2 protein and stabilize it, enhancing its effect on HDAC1 and Hh pathway. KCTD15 and KCTD1 proteins share a high homology and are clustered in a specific KCTD subfamily. We characterize here KCTD1 role on the Hh pathway. Therefore, we demonstrated KCTD1 interaction with KCASH1 and KCASH2 proteins, and its role in their stabilization by reducing their ubiquitination and proteasome-mediated degradation. Consequently, KCTD1 expression reduces HDAC1 protein levels and Hh/Gli1 activity, inhibiting Hh dependent cell proliferation in Hh tumour cells. Furthermore, analysis of expression data on publicly available databases indicates that KCTD1 expression is reduced in Hh dependent MB samples, compared to normal cerebella, suggesting that KCTD1 may represent a new putative target for therapeutic approaches against Hh-dependent tumour.

Beyond base pairs to bedside: a population perspective on how genomics can improve health.

A decade after the sequencing of the human genome, the National Human Genome Research Institute announced a strategic plan for genomic medicine. It calls for evaluating the structure and biology of genomes, understanding the biology of disease, advancing the science of medicine, and improving the effectiveness of health care. Fulfilling the promise of genomics urgently requires a population perspective to complement the bench-to-bedside model of translation. A population approach should assess the contribution of genomics to health in the context of social and environmental determinants of disease; evaluate genomic applications that may improve health care; design strategies for integrating genomics into practice; address ethical, legal, and social issues; and measure the population health impact of new technologies.

A clinical evaluation of four non-Luer spinal needle and syringe systems.

We performed an evaluation of non-Luer spinal devices supplied by four manufacturers or suppliers: Polymedic; Pajunk; Sarstedt; and Smiths. For each supplier, 100 evaluations were performed using a 25-G 90-mm spinal needle, 3-ml syringe, 5-ml syringe and filter needle; for comparison, 100 evaluations were performed with our standard Luer equipment. The non-Luer devices were associated with more qualitative problems compared with the Luer devices, for example, poor feel of dural puncture (9-32% vs 10%, respectively), poor observation of cerebrospinal fluid in the hub (3-27% vs 0%), and connection problem of the syringe to the spinal needle (7-33% vs 0%). There was also more frequent failure to achieve the spinal injection due to equipment-related causes (4-7% vs 0%, respectively). Median (IQR [range]) numeric satisfaction scores for the spinal needles were: Luer 10 (9-10 [7-10]); Polymedic 7 (4-8 [0-10]; Pajunk 7 (5-8 [0-10]); Sarstedt 7 (6-8 [0-10]); and Smiths 9 (7-10 [0-10]) (p<0.0001). Satisfaction scores for all spinal equipment were: Luer 10 (9-10 [5-10]); Polymedic 8 (6-8 [0-10]); Pajunk 7 (5-7 [1-9]); Sarstedt 8 (6-8 [0-10]); and Smiths 8 (8-9 [2-10]) (p<0.0001). Between 21% and 75% of non-Luer evaluations were rated with satisfaction worse than the usual Luer needle compared with 0-10% rated better, depending on the needle type. Between 22% and 76% of non-Luer evaluations were rated with satisfaction worse than the usual Luer equipment compared with 0-14% rated better. Specific concerns included poor feel of tissue planes and observation of cerebrospinal fluid (Polymedic), difficulty with connection of the syringe to the spinal needle and trocar removal (Pajunk), poor feel of tissue planes and needle flexibility (Sarstedt) and difficulty with connection of the syringe to the spinal needle (Smiths). We could not demonstrate a short-term learning curve for the new devices. Decisions on purchasing and implementation of the new non-Luer equipment will have to acknowledge that clinicians may have greater technical problems and reduced satisfaction compared with the current equipment.

Sequencing and phylogenetic analysis of the coding region of six common rotavirus strains: evidence for intragenogroup reassortment among co-circulating G1P[8] and G2P[4] strains from the United States.

The segmented genome of rotaviruses provides an opportunity for rotavirus strains to generate a large genetic diversity through reassortment; however, this mechanism is considered to play little role in the generation of mosaic gene constellations between Wa-like and DS-1-like strains in genes other than the neutralization antigens. A pilot study was undertaken to analyze these two epidemiologically important strains at the genomic level in order to (i) identify intergenogroup reassortment and (ii) to make available additional reference genome sequences of G1P[8] and G2P[4] for future genomics analyses. The full or nearly complete coding region of all 11 genes for 3 G1P[8] (LB2719, LB2758, and LB2771) and 3 G2P[4] (LB2744, LB2764, and LB2772) strains isolated from children hospitalized with severe diarrhea in Long Beach, California, where these strains were circulating at comparable rates during 2005-2006 are described in this study. Based on the full-genome classification system, all G1P[8] strains had a conserved genomic constellation: G1-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-E1-H1 and were mostly identical to the few Wa-like strains whose genome sequences have already been determined. Similarly, the genome sequences of the 3 G2P[4] strains were highly conserved: G2-P[4]-I2-R2-C2-M2-A2-N2-T2-E2-E2-H2 and displayed an overall lesser genetic divergence with reference DS-1-like strains. While intergenogroup reassortment was not seen between the G1P[8] and G2P[4] strains studied here, evidence for intragenogroup reassortment events was identified. Similar studies in the post-rotavirus genomic era will help uncover whether intergenogroup reassortment affecting the backbone genes could play a significant role in any potential vaccine breakthrough events by evading immunity of vaccinated children.