Connexin hemichannels drive lactation-induced osteocyte acidification and perilacunar-canalicular remodeling.

The maternal skeleton experiences significant bone loss during lactation, followed by rapid restoration post weaning. Parathyroid-related protein (PTHrP)-induced acidification of the perilacunar matrix by osteocytes is crucial in this process, yet its mechanism remains unclear. Here, we identify Cx43 hemichannels (HCs) as key mediators of osteocyte acidification and perilacunar-canalicular remodeling (PLR). Utilizing transgenic mouse models expressing dominant-negative Cx43 mutants, we show that mice with impaired Cx43 HCs exhibit attenuated lactation-induced responses compared to wild-type and only gap junction-impaired groups, including lacunar enlargement, upregulation of PLR genes, and bone loss with compromised mechanical properties. Furthermore, inhibition of HCs by a Cx43 antibody blunts PTHrP-induced calcium influx and protein kinase A activation, followed by impaired osteocyte acidification. Additionally, impeded HCs suppress bone recovery during the post-lactation period. Our findings highlight the pivotal role of Cx43 HCs in orchestrating dynamic bone changes during lactation and recovery by regulating acidification and remodeling enzyme expression.

Are biomarkers associated with sensitivity to physical activity?

BACKGROUND: Activity-based treatments play an integral role in managing musculoskeletal conditions including low back pain. However, while therapeutic exercise has been shown to reduce pain in such conditions, certain individuals experience a paradoxical pain increase in response to exercise. The physiological processes underlying this sensitivity to physical activity (SPA) are not fully understood, however stress and inflammation have been shown to contribute to SPA. The present cross-sectional study investigated whether physiological indicators of stress (cortisol) and inflammation (IL-6) help explain SPA. METHODS: Twenty-seven patients with chronic low back pain and 21 healthy controls completed a 1-h exercise session of standardized physical tasks. SPA was calculated from the difference between post- and pre-exercise pain levels. Participant's saliva was collected at several timepoints for cortisol and IL-6 levels quantification. Their waking cortisol response was calculated to reflect their cortisol regulation. Reactivity of IL-6 and cortisol was calculated to reflect changes in these measures during exercise. RESULTS: IL-6 reactivity was significantly and positively correlated with SPA among participants with low back pain. In contrast, neither cortisol waking response nor cortisol reactivity was significantly correlated within the low back pain group. No significant differences in IL-6 reactivity, cortisol reactivity or cortisol waking response were observed. CONCLUSION: These findings are the first to link SPA to an objective biomarker among people with low back pain. These findings help describe the physiological mechanisms of SPA and can support new clinical research that targets the inflammatory response of patients with chronic low-back pain and elevated SPA. SIGNIFICANCE: This study reveals a correlation between SPA and an objective salivary biomarker of IL-6 in people with low back pain, improving our understanding of this clinically relevant subjective experience.

[Stereotactic body radiation therapy for primary kidney cancer]. / Radiothérapie stéréotaxique des carcinomes rénaux primitifs.

The incidence of primary renal cancer is increasing, particularly in elderly patients who may have comorbidities and/or a surgical contraindications. Stereotactic body radiotherapy has primarily been evaluated retrospectively to date. The most commonly used dose schedules are 40Gy in five fractions, 42Gy in three fractions, and 26Gy in one fraction. The results in terms of local control and toxicity are very encouraging. The advantages of stereotactic body radiotherapy compared to thermal ablative treatments are its non-invasive nature, absence of general anesthesia, ability to treat larger lesions, and those close to the renal hilum. Prospective evaluations are still necessary.

Task-based measures of sensitivity to physical activity predict daily life pain and mood among people living with back pain.

BACKGROUND: Clinical interventions aim to improve the daily life experiences of patients. However, past research has highlighted important discrepancies between commonly used assessments (e.g. retrospective questionnaires) and patients' daily life experiences of pain. These gaps may contribute to flawed clinical decision-making and ineffective care. Recent work suggests that real-time, task-based clinical assessments may help reduce these discrepancies by adding predictive value in explaining daily life pain experiences. This study aimed to investigate these relationships by evaluating whether task-based measures of sensitivity to physical activity (SPA) predict daily life pain and mood, beyond traditional pain-related questionnaires. METHODS: Adults with back pain (<6-month onset) answered pain-related questionnaires and completed a standardized lifting task. SPA-Pain, SPA-Sensory and SPA-Mood were, respectively, assessed as task-evoked changes in pain intensity, pressure pain threshold (back, hands), situational catastrophizing. Over the next 9 days, daily life pain and mood were assessed using smartphone-based ecological momentary assessment (EMA-Pain and EMA-Mood, respectively) with stratified random sampling. Data analyses estimated fixed effects (b) using multilevel linear modelling with random intercepts. RESULTS: Median EMA completion per participant was 66.67% (n = 67 participants). After controlling for covariates, SPA-Pain was associated with EMA-Pain (b = 0.235, p = 0.002) and SPA-Psych approached significance with EMA-Mood (b = -0.159, p = 0.052). CONCLUSIONS: Task-based assessment of SPA helps explain daily life pain and mood among adults with back pain, beyond traditional questionnaires. Adding task-based assessment of SPA may achieve a more complete picture of pain and mood in daily life, offering clinicians better guidance when prescribing activity-based interventions that are designed to modify daily life behaviour, such as graded activity. SIGNIFICANCE: This study found that, among people with back pain, task-based measures of sensitivity to physical activity contribute additional predictive value for daily life pain and mood beyond self-report questionnaires. Findings suggest that real-time, task-based measures may help mitigate some of the shortcomings that are commonly associated with retrospective questionnaires.

A Meta-Analysis of Group Cognitive Behavioral Therapy and Group Psychoeducation for Treating Symptoms and Preventing Relapse in People Living with Bipolar Disorder.

Objectives: This meta-analysis aims to evaluate the treatment outcomes of patients treated with Group cognitive behavioural therapy (GCBT) or group psychoeducation (GPE) as an adjunct to pharmacotherapy. Methods: Systematic search of PubMed, EMBASE, PsycINFO, and CENTRAL from inception till 1 March 2022 was conducted. Randomized-controlled-trials (RCTs) comparing GCBT/GPE with controls (treatment-as-usual/individualized therapy) in adults with bipolar disorder were eligible. The outcomes were relapse rates of any depressive or manic episodes and control of depressive and manic symptoms post-intervention. Overall odds-ratio was used to evaluate the relapse rates. Standard Mean Differences were pooled using a random-effects model for the control of depressive and manic symptoms. Results: 25 articles were assessed full-text independently by two members, and 11 studies were included in this meta-analysis. 601 and 590 participants were randomized into group-therapy (GCBT/GPE) and control, respectively. GPE significantly reduces relapse rates at post-intervention with Odds ratio of 0.43 (95% CI = 0.28-to-0.62, p < 0.0001) (I² = 41%) compared to control, however, no significant results were found for GPE on control of depressive or manic symptoms. No significant results were found for GCBT in all outcomes. Conclusion: This meta-analysis provides some evidence that GPE could be an efficacious treatment as an adjunct to treatment-as-usual in reducing the relapse rates of patients with bipolar disorder.

TH-MYCN tumors, but not tumor-derived cell lines, are adrenergic lineage, GD2+, and responsive to anti-GD2 antibody therapy.

Neuroblastoma is a commonly lethal solid tumor of childhood and intensive chemoradiotherapy treatment cures ~50% of children with high-risk disease. The addition of immunotherapy using dinutuximab, a monoclonal antibody directed against the GD2 disialoganglioside expressed on neuroblasts, improves survival when incorporated into front-line therapy and shows robust activity in regressing relapsed disease when combined with chemotherapy. Still, many children succumb to neuroblastoma progression despite receiving dinutuximab-based immunotherapy, and efforts to counteract the immune suppressive signals responsible are warranted. Animal models of human cancers provide useful platforms to study immunotherapies. TH-MYCN transgenic mice are immunocompetent and develop neuroblastomas at autochthonous sites due to enforced MYCN expression in developing neural crest tissues. However, GD2-directed immunotherapy in this model has been underutilized due to the prevailing notion that TH-MYCN neuroblasts express insufficient GD2 to be targeted. We demonstrate that neuroblasts in TH-MYCN-driven tumors express GD2 at levels comparable to human neuroblastomas but rapidly lose GD2 expression when explanted ex vivo to establish tumor cell lines. This occurs in association with a transition from an adrenergic to mesenchymal differentiation state. Importantly, not only is GD2 expression retained on tumors in situ, treatment with a murine anti-GD2 antibody, 14G2a, markedly extends survival in such mice, including durable complete responses. Tumors in 14G2a-treated mice have fewer macrophage and myeloid-derived suppressor cells in their tumor microenvironment. Our findings support the utility of this model to inform immunotherapy approaches for neuroblastoma and potential opportunities to investigate drivers of adrenergic to mesenchymal fate decisions.

Theoretical guidelines for editing ecological communities.

Having control over species abundances and community resilience is of great interest for experimental, agricultural, industrial and conservation purposes. Here, we theoretically explore the possibility of manipulating ecological communities by modifying pairwise interactions. Specifically, we establish which interaction values should be modified, and by how much, in order to alter the composition or resilience of a community towards a favorable direction. While doing so, we also take into account the experimental difficulties in making such modifications by including in our optimization process, a cost parameter, which penalizes large modifications. In addition to prescribing what changes should be made to interspecies interactions given some modification cost, our approach also serves to establish the limits of community control, i.e. how well can one approach an ecological goal at best, even when not constrained by cost.

Chrysosplenol-C Increases Contraction by Augmentation of Sarcoplasmic Reticulum Ca2+ Loading and Release via Protein Kinase C in Rat Ventricular Myocytes.

Naturally found chrysosplenol-C (4',5,6-trihydroxy-3,3',7-trimethoxyflavone) increases the contractility of cardiac myocytes independent of ß-adrenergic signaling. We investigated the cellular mechanism for chrysosplenol-C-induced positive inotropy. Global and local Ca2+ signals, L-type Ca2+ current (ICa), and contraction were measured from adult rat ventricular myocytes using two-dimensional confocal Ca2+ imaging, the whole-cell patch-clamp technique, and video-edge detection, respectively. Application of chrysosplenol-C reversibly increased Ca2+ transient magnitude with a maximal increase of ∼55% within 2- to 3-minute exposures (EC50 ≅ 21 µM). This chemical did not alter ICa and slightly increased diastolic Ca2+ level. The frequency and size of resting Ca2+ sparks were increased by chrysosplenol-C. Chrysosplenol-C significantly increased sarcoplasmic reticulum (SR) Ca2+ content but not fractional release. Pretreatment of protein kinase C (PKC) inhibitor but not Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor abolished the stimulatory effects of chrysosplenol-C on Ca2+ transients and Ca2+ sparks. Chrysosplenol-C-induced positive inotropy was removed by the inhibition of PKC but not CaMKII or phospholipase C. Western blotting assessment revealed that PKC-δ protein level in the membrane fractions significantly increase within 2 minutes after chrysosplenol-C exposure with a delayed (5-minute) increase in PKC-α levels in insoluble membrane. These results suggest that chrysosplenol-C enhances contractility via PKC (most likely PKC-δ)-dependent enhancement of SR Ca2+ releases in ventricular myocytes. SIGNIFICANCE STATEMENT: Study shows that chrysosplenol-C, a natural flavone showing a positive inotropic effect, increases SR Ca2+ releases on depolarizations and Ca2+ sparks with an increase of SR Ca2+ loading but not L-type Ca2+ current in ventricular myocytes. Chrysosplenol-C-induced enhancement in contraction is eliminated by PKC inhibition, and it is associated with redistributions of PKC to the membrane. These indicate that chrysosplenol-C enhances contraction via PKC-dependent augmentations of SR Ca2+ release and Ca2+ loading during action potentials.

Prevalence and genotype distribution of JC polyomavirus in urine from patients with hematological malignancies in Vietnam.

JC virus (JCV) causes progressive multifocal leukoencephalopathy in immunocompromised patients. The prevalence and genotype patterns of JCV vary between different geographical regions. This study was done to investigate the prevalence and genotype distribution of JCV in patients with hematological malignancies in Vietnam. A total of 48 urine samples were collected from patients with hematological malignancies. DNA was extracted and detection of JCV was by nested-polymerase chain reaction. Sequence analysis was obtained and a phylogenetic tree was constructed for genotyping of JCV. Twenty-seven (56.25%) urine samples tested positive for JCV. JCV genotype 7 was only observed in this study. Subtype analysis showed that JCV subtype 7A was the most commonly prevalent, followed by 7B1 and 7C1. Other subtypes were not detected in this population. There were no significant differences associated with age, gender, and biochemical parameters between patients with JCV and without JCV excretion in urine. The present study showed a high prevalence of JCV in the urine of patients with hematologic malignancies. The most common genotype found in this population was JCV subtype 7A.

Extinction in complex communities as driven by adaptive dynamics.

In a complex community, species continuously adapt to each other. On rare occasions, the adaptation of a species can lead to the extinction of others, and even its own. 'Adaptive dynamics' is the standard mathematical framework to describe evolutionary changes in community interactions, and in particular, predict adaptation driven extinction. Unfortunately, most authors implement the equations of adaptive dynamics through computer simulations that require assuming a large number of questionable parameters and fitness functions. In this study, we present analytical solutions to adaptive dynamics equations, thereby clarifying how outcomes depend on any computational input. We develop general formulas that predict equilibrium abundances over evolutionary time scales. Additionally, we predict which species will go extinct next, and when this will happen.

Guided by gaze: Prioritization strategy when navigating through a virtual crowd can be assessed through gaze activity.

Modelling crowd behavior is essential for the management of mass events and pedestrian traffic. Current microscopic approaches consider the individual's behavior to predict the effect of individual actions in local interactions on the collective scale of the crowd motion. Recent developments in the use of virtual reality as an experimental tool have offered an opportunity to extend the understanding of these interactions in controlled and repeatable settings. Nevertheless, based on kinematics alone, it remains difficult to tease out how these interactions unfold. Therefore, we tested the hypothesis that gaze activity provides additional information about pedestrian interactions. Using an eye tracker, we recorded the participant's gaze behavior whilst navigating through a virtual crowd. Results revealed that gaze was consistently attracted to virtual walkers with the smallest values of distance at closest approach (DCA) and time to closest approach (TtCA), indicating a higher risk of collision. Moreover, virtual walkers gazed upon before an avoidance maneuver was initiated had a high risk of collision and were typically avoided in the subsequent avoidance maneuver. We argue that humans navigate through crowds by selecting only few interactions and that gaze reveals how a walker prioritizes these interactions. Moreover, we pose that combining kinematic and gaze data provides new opportunities for studying how interactions are selected by pedestrians walking through crowded dynamic environments.

HIV and viral hepatitis coinfection analysis using surveillance data from 15 US states and two cities.

Coinfection with human immunodeficiency virus (HIV) and viral hepatitis is associated with high morbidity and mortality in the absence of clinical management, making identification of these cases crucial. We examined characteristics of HIV and viral hepatitis coinfections by using surveillance data from 15 US states and two cities. Each jurisdiction used an automated deterministic matching method to link surveillance data for persons with reported acute and chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections, to persons reported with HIV infection. Of the 504 398 persons living with diagnosed HIV infection at the end of 2014, 2.0% were coinfected with HBV and 6.7% were coinfected with HCV. Of the 269 884 persons ever reported with HBV, 5.2% were reported with HIV. Of the 1 093 050 persons ever reported with HCV, 4.3% were reported with HIV. A greater proportion of persons coinfected with HIV and HBV were males and blacks/African Americans, compared with those with HIV monoinfection. Persons who inject drugs represented a greater proportion of those coinfected with HIV and HCV, compared with those with HIV monoinfection. Matching HIV and viral hepatitis surveillance data highlights epidemiological characteristics of persons coinfected and can be used to routinely monitor health status and guide state and national public health interventions.

Feasibility and acceptability of a universal screening and referral protocol for gender-based violence with women seeking care in health clinics in Dadaab refugee camps in Kenya.

BACKGROUND: Gender-based violence (GBV) is both a global public health problem and violation of human rights. Refugees and internally displaced persons experience an increased risk of GBV and health outcomes associated with GBV are often exacerbated in conflict settings. METHODS: A mixed methods study to examine the feasibility and acceptability of universal screening for GBV in a refugee population in the Dadaab refugee camp of Kenya, using the ASIST-GBV from January to July 2015. RESULTS: Of 9366 women offered screening at International Rescue Committee health clinics, about 89% (n = 8369) female refugees consented to participate. Only 15% of the potentially eligible population could participate in GBV screening because of the ongoing struggle to identify private space in the clinics. Over 85% of women reported being 'willing' or 'very willing' to participate in GBV screening; 96% felt they had a good or very good experience with the screening protocol. Qualitative findings stressed the importance of securing a room/space in the busy clinic is critical to universal screening with referral to safe and confidential services for survivors. CONCLUSIONS: The findings suggest that the evidence-based ASIST-GBV is both feasible to implement and acceptable to both providers and women seeking care. Universal GBV screening and referral is an effective way for health care and service providers in humanitarian settings to assist survivors of GBV.

Heterogeneity of anatomic regions by MR volumetry in juvenile myoclonic epilepsy.

OBJECTIVE: To investigate brain volumes in patients with well-characterized juvenile myoclonic epilepsy (JME). MATERIALS AND METHODS: We studied the MRI images of seventeen subjects with EEG and clinically defined JME and seventeen age- and sex-matched controls using voxel-based morphometry (VBM) and automated and manual volumetry. RESULTS: We found no significant group differences in the cortical volumes by automated techniques for all regions or for the whole brain. However, we found a larger pulvinar nucleus in JME using VBM with small volume correction and a larger thalamus with manual volumetry (P = 0.001; corrected two-tailed t-test). By analysing the individual subjects, we determined that considerable heterogeneity exists even in this highly selected group. Histograms of all JME and matched control regions' volumes showed more subjects with JME had smaller hippocampi and larger thalami (P < 0.05; chi-square). Subjects in whom the first seizure was absence were more likely to have smaller hippocampi than their matched control, while those without absences showed no differences (P < 0.05, chi-square). CONCLUSIONS: There is ample evidence for frontal cortical thalamic network changes in JME, but subcortical structural differences were more distinct in this group. Given the heterogeneity of brain volumes in the clinical population, further advancement in the field will require the examination of stringent genetically controlled populations.

Unconventional magnetisation texture in graphene/cobalt hybrids.

Magnetic domain structure and spin-dependent reflectivity measurements on cobalt thin films intercalated at the graphene/Ir(111) interface are investigated using spin-polarised low-energy electron microscopy. We find that graphene-covered cobalt films have surprising magnetic properties. Vectorial imaging of magnetic domains reveals an unusually gradual thickness-dependent spin reorientation transition, in which magnetisation rotates from out-of-the-film plane to the in-plane direction by less than 10° per cobalt monolayer. During this transition, cobalt films have a meandering spin texture, characterised by a complex, three-dimensional, wavy magnetisation pattern. In addition, spectroscopy measurements suggest that the electronic band structure of the unoccupied states is essentially spin-independent already a few electron-Volts above the vacuum level. These properties strikingly differ from those of pristine cobalt films and could open new prospects in surface magnetism.

Comprehensive development and testing of the ASIST-GBV, a screening tool for responding to gender-based violence among women in humanitarian settings.

BACKGROUND: Conflict affected refugees and internally displaced persons (IDPs) are at increased vulnerability to gender-based violence (GBV). Health, psychosocial, and protection services have been implemented in humanitarian settings, but GBV remains under-reported and available services under-utilized. To improve access to existing GBV services and facilitate reporting, the ASIST-GBV screening tool was developed and tested for use in humanitarian settings. This process was completed in four phases: 1) systematic literature review, 2) qualitative research that included individual interviews and focus groups with GBV survivors and service providers, respectively, 3) pilot testing of the developed screening tool, and 4) 3-month implementation testing of the screening tool. Research was conducted among female refugees, aged ≥15 years in Ethiopia, and female IDPs, aged ≥18 years in Colombia. RESULTS: The systematic review and meta-analysis identified a range of GBV experiences and estimated a 21.4 % prevalence of sexual violence (95 % CI:14.9-28.7) among conflict-affected populations. No existing screening tools for GBV in humanitarian settings were identified. Qualitative research with GBV survivors in Ethiopia and Colombia found multiple forms of GBV experienced by refugees and IDPs that occurred during conflict, in transit, and in displaced settings. Identified forms of violence were combined into seven key items on the screening tool: threats of violence, physical violence, forced sex, sexual exploitation, forced pregnancy, forced abortion, and early or forced marriage. Cognitive testing further refined the tool. Pilot testing in both sites demonstrated preliminary feasibility where 64.8 % of participants in Ethiopia and 44.9 % of participants in Colombia were identified with recent (last 12 months) cases of GBV. Implementation testing of the screening tool, conducted as a routine service in camp/district hospitals, allowed for identification of GBV cases and referrals to services. In this phase, 50.6 % of participants in Ethiopia and 63.4 % in Colombia screened positive for recent experiences of GBV. Psychometric testing demonstrated appropriate internal consistency of the tool (Cronbach's α = 0.77) and item response theory demonstrated appropriate discrimination and difficulty of the tool. CONCLUSION: The ASIST-GBV screening tool has demonstrated utility and validity for use in confidential identification and referral of refugees and IDPs who experience GBV.

Applications of dual energy computed tomography in abdominal imaging.

Dual energy computed tomography (CT) is an imaging technique based on data acquisition at two different energy settings. Recent advances in CT have allowed data acquisition and almost simultaneously analysis of two spectra of X-rays at different energy levels resulting in novel developments in the field of abdominal imaging. This technique is widely used in cardiovascular imaging, especially for pulmonary embolism work-up but is now also increasingly developed in the field of abdominal imaging. With dual-energy CT it is possible to obtain virtual unenhanced images from monochromatic reconstructions as well as attenuation maps of different elements, thereby improving detection and characterization of a variety of renal, adrenal, hepatic and pancreatic abnormalities. Also, dual-energy CT can provide information regarding urinary calculi composition. This article reviews and illustrates the different applications of dual-energy CT in routine abdominal imaging.

Narrow band imaging: clinical applications in oral and oropharyngeal cancer.

Narrow Band Imaging (NBI) is an endoscopic optical imaging enhancement technology that improves the contrast of mucosal surface texture, and enhances visualisation of mucosal and submucosal vasculature. White light is filtered to emit two 30-nm narrow bands of blue (415 nm) and green light (540 nm) light simultaneously, the former corresponding to the main peak absorption spectrum of haemoglobin, and the latter allowing visualisation of blood vessels in the deeper mucosal and submucosal layers. NBI has been used to better assess oral potentially malignant disorders (OPMD), identify oral and oropharyngeal squamous cell carcinoma (SCC), and to define surgical margins of head and neck malignancies. NBI shows great potential in improving detection rates of OPMD, facilitating better assessment of oral and oropharyngeal SCC, and reducing the risk of recurrence for oral SCC. Although further research is required to better understand and define intrapapillary capillary loop (IPCL) patterns and to relate these with clinical, histopathological and molecular parameters especially for early mucosal changes, there is building evidence to recommend its use as the new gold standard for endoscopic assessment in head and neck oncology.

Polyoxygenated steroids from the gorgonian Menella woodin with capabilities to modulate ROS levels in macrophages at response to LPS.

Four new polyoxygenated sterol derivatives (1-4) along with the compounds (5-7) previously known from other biological sources were isolated from the gorgonian Menella woodin, collected from the Vietnamese waters. Structures of 1-4 were elucidated by the detailed NMR spectroscopic and mass-spectrometric analyses as well as comparison with those reported in literature data. Compounds 1, 4, and 6 decrease the production of reactive oxygen species (ROS) by the murine macrophages of RAW 264.7 line at induction by endotoxic lipopolysaccharide (LPS) from Escherichia coli.