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Traumatic skeletal muscle injuries cause irreversible tissue damage and impaired revascularization. Engineered muscle is promising for enhancing tissue revascularization and regeneration in injured muscle. Here we fabricated engineered skeletal muscle composed of myotubes interspersed with vascular endothelial cells using spatially patterned scaffolds that induce aligned cellular organization, and then assessed their therapeutic benefit for treatment of murine volumetric muscle loss. Murine skeletal myoblasts co-cultured with endothelial cells in aligned nanofibrillar scaffolds form endothelialized and aligned muscle with longer myotubes, more synchronized contractility, and more abundant secretion of angiogenic cytokines, compared to endothelialized engineered muscle formed from randomly-oriented scaffolds. Treatment of traumatically injured muscle with endothelialized and aligned skeletal muscle promotes the formation of highly organized myofibers and microvasculature, along with greater vascular perfusion, compared to treatment of muscle derived from randomly-oriented scaffolds. This work demonstrates the potential of endothelialized and aligned engineered skeletal muscle to promote vascular regeneration following transplantation. Karina Nakayama et al. bioengineer endothelialized mouse skeletal muscle using parallel-aligned nanofibrillar scaffolds. They find that muscle produced using the aligned scaffolds developed a spatially patterned structure and showed improved endothelial interaction compared to muscle engineered with randomly-oriented scaffolds.

Traumatic skeletal muscle injuries cause irreversible tissue damage and impaired revascularization. Engineered muscle is promising for enhancing tissue revascularization and regeneration in injured muscle. Here we fabricated engineered skeletal muscle composed of myotubes interspersed with vascular endothelial cells using spatially patterned scaffolds that induce aligned cellular organization, and then assessed their therapeutic benefit for treatment of murine volumetric muscle loss. Murine skeletal myoblasts co-cultured with endothelial cells in aligned nanofibrillar scaffolds form endothelialized and aligned muscle with longer myotubes, more synchronized contractility, and more abundant secretion of angiogenic cytokines, compared to endothelialized engineered muscle formed from randomly-oriented scaffolds. Treatment of traumatically injured muscle with endothelialized and aligned skeletal muscle promotes the formation of highly organized myofibers and microvasculature, along with greater vascular perfusion, compared to treatment of muscle derived from randomly-oriented scaffolds. This work demonstrates the potential of endothelialized and aligned engineered skeletal muscle to promote vascular regeneration following transplantation.

Many organisations promote eHealth applications as a feasible, low-cost method of addressing mental ill-health and stress amongst their employees. However, there are good reasons why the efficacy identified in clinical or other samples may not generalize to employees, and many Apps are being developed specifically for this group. The aim of this paper is to conduct the first comprehensive systematic review and meta-analysis evaluating the evidence for the effectiveness and examine the relative efficacy of different types of eHealth interventions for employees. Systematic searches were conducted for relevant articles published from 1975 until November 17, 2016, of trials of eHealth mental health interventions (App or web-based) focused on the mental health of employees. The quality and bias of all identified studies was assessed. We extracted means and standard deviations from published reports, comparing the difference in effect sizes (Hedge's g) in standardized mental health outcomes. We meta-analysed these using a random effects model, stratified by length of follow up, intervention type, and whether the intervention was universal (unselected) or targeted to selected groups e.g. \"stressed\". 23 controlled trials of eHealth interventions were identified which overall suggested a small positive effect at both post intervention (g = 0.24, 95% CI 0.13 to 0.35) and follow up (g = 0.23, 95% CI 0.03 to 0.42). There were differential short term effects seen between the intervention types whereby Mindfulness based interventions (g = 0.60, 95% CI 0.34 to 0.85, n = 6) showed larger effects than the Cognitive Behaviour Therapy (CBT) based (g = 0.15, 95% CI 0.02 to 0.29, n = 11) and Stress Management based (g = 0.17, 95%CI -0.01 to 0.34, n = 6) interventions. The Stress Management interventions however differed by whether delivered to universal or targeted groups with a moderately large effect size at both post-intervention (g = 0.64, 95% CI 0.54 to 0.85) and follow-up (g = 0.69, 95% CI 0.06 to 1.33) in targeted groups, but no effect in unselected groups. There is reasonable evidence that eHealth interventions delivered to employees may reduce mental health and stress symptoms post intervention and still have a benefit, although reduced at follow-up. Despite the enthusiasm in the corporate world for such approaches, employers and other organisations should be aware not all such interventions are equal, many lack evidence, and achieving the best outcomes depends upon providing the right type of intervention to the correct population.

Managers are in an influential position to make decisions that can impact on the mental health and well-being of their employees. As a result, there is an increasing trend for organisations to provide managers with training in how to reduce work-based mental health risk factors for their employees. A systematic search of the literature was conducted to identify workplace interventions for managers with an emphasis on the mental health of employees reporting directing to them. A meta-analysis was performed to calculate pooled effect sizes using the random effects model for both manager and employee outcomes. Ten controlled trials were identified as relevant for this review. Outcomes evaluating managers’ mental health knowledge (standardised mean difference (SMD)=0.73; 95% CI 0.43 to 1.03; p<0.001), non-stigmatising attitudes towards mental health (SMD=0.36; 95% CI 0.18 to 0.53; p<0.001) and improving behaviour in supporting employees experiencing mental health problems (SMD=0.59; 95% CI 0.14 to 1.03; p=0.01) were found to have significant pooled effect sizes favouring the intervention. A significant pooled effect was not found for the small number of studies evaluating psychological symptoms in employees (p=0.28). Our meta-analysis indicates that training managers in workplace mental health can improve their knowledge, attitudes and self-reported behaviour in supporting employees experiencing mental health problems. At present, any findings regarding the impact of manager training on levels of psychological distress among employees remain preliminary as only a very limited amount of research evaluating employee outcomes is available. Our review suggests that in order to understand the effectiveness of manager training on employees, an increase in collection of employee level data is required.

Cells deficient in the Brca1 and Brca2 genes have reduced capacity to repair DNA double-strand breaks by homologous recombination and consequently are hypersensitive to DNA-damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP, protects Brca1/2 -deficient cells from DNA damage and rescues the lethality of Brca2 -deficient embryonic stem cells. However, PTIP deficiency does not restore homologous recombination activity at double-strand breaks. Instead, its absence inhibits the recruitment of the MRE11 nuclease to stalled replication forks, which in turn protects nascent DNA strands from extensive degradation. More generally, acquisition of PARP inhibitors and cisplatin resistance is associated with replication fork protection in Brca2 -deficient tumour cells that do not develop Brca2 reversion mutations. Disruption of multiple proteins, including PARP1 and CHD4, leads to the same end point of replication fork protection, highlighting the complexities by which tumour cells evade chemotherapeutic interventions and acquire drug resistance. Protection of nascent DNA from degradation provides a mechanism that can promote synthetic viability and drug resistance in Brca -deficient cells without restoring homologous recombination at double-strand breaks. Chemoresistance in BRCA cancers The breast cancer susceptibility genes BRCA1 and BRCA2 function to protect the genome from DNA damage. For this reason, DNA-damaging agents are used clinically to treat BRCA -deficient cancers. However, these treatments may have a short window of effectiveness; many cancers develop resistance. André Nussenzweig and colleagues show that cells become drug resistant due to loss of the PTIP protein. In its absence, forks that stall during DNA replication are protected from degradation, and this allows the cells to survive. This work highlights a previously unknown mechanism by which resistance to cancer therapy can arise.

Background Primary orthostatic tremor (OT) is a rare movement disorder characterized by a 13–18 Hz leg tremor, which arises when standing and is relieved by walking/sitting. Those affected generally do not fall, but experience fear of falling, lessened by ambulation. Because of its low amplitude, the tremor is not readily visible, and diagnosis requires confirmation with surface electromyography (sEMG). Recently, applications using the accelerometer feature of smartphones have been used to detect and quantify tremors, including OT, though the accuracy of smartphone accelerometry (SPA) in diagnosing OT is unknown. Methods We completed SPA in consecutive adults (18+ years), who presented to our neurology clinic with either subjective leg shakiness upon standing or unsteadiness when standing that lessened with ambulation, which comprised 59 of 2578 patients. We assessed tremor using the StudyMyTremor application on an iPhone 6 s adhered with tape to the patient’s tibialis anterior. Surface electromyography was completed on the same muscle. The primary outcome of this study was to determine SPA’s sensitivity and specificity in detecting OT compared with surface electromyography. Results Fifty-nine patients with the following diagnoses were included: OT (6), Parkinson’s disease, Hereditary Spastic Paraplegia, orthostatic hypotension, essential tremor, spinal cerebellar ataxia, sensory ataxia and functional movement disorder. Smartphone accelerometry detected a 13–18 Hz tremor in 5 of 6 patients diagnosed with OT by sEMG with no false positives in other conditions, yielding a sensitivity of 83%, specificity of 100% in the cohort we studied. Conclusions Though a larger sample size is desirable, preliminary data suggest that smartphone accelerometry is an alternative to surface electromyography in diagnosing OT.

There is evidence that depression can be prevented; however, traditional approaches face significant scalability issues. Digital technologies provide a potential solution, although this has not been adequately tested. The aim of this study was to evaluate the effectiveness of a new smartphone app designed to reduce depression symptoms and subsequent incident depression amongst a large group of Australian workers. A randomized controlled trial was conducted with follow-up assessments at 5 weeks and 3 and 12 months post-baseline. Participants were employed Australians reporting no clinically significant depression. The intervention group (N = 1128) was allocated to use HeadGear, a smartphone app which included a 30-day behavioural activation and mindfulness intervention. The attention-control group (N = 1143) used an app which included a 30-day mood monitoring component. The primary outcome was the level of depressive symptomatology (PHQ-9) at 3-month follow-up. Analyses were conducted within an intention-to-treat framework using mixed modelling. Those assigned to the HeadGear arm had fewer depressive symptoms over the course of the trial compared to those assigned to the control (F3,734.7 = 2.98, p = 0.031). Prevalence of depression over the 12-month period was 8.0% and 3.5% for controls and HeadGear recipients, respectively, with odds of depression caseness amongst the intervention group of 0.43 (p = 0.001, 95% CI 0.26-0.70). This trial demonstrates that a smartphone app can reduce depression symptoms and potentially prevent incident depression caseness and such interventions may have a role in improving working population mental health. Some caution in interpretation is needed regarding the clinical significance due to small effect size and trial attrition.Trial Registration Australian and New Zealand Clinical Trials Registry (www.anzctr.org.au/) ACTRN12617000548336.

Brucellosis, caused by Brucella abortus, is a major disease of cattle and humans worldwide distributed. Eradication and control of the disease has been difficult in Central and South America, Central Asia, the Mediterranean and the Middle East. Epidemiological strategies combined with phylogenetic methods provide the high-resolution power needed to study relationships between surveillance data and pathogen population dynamics, using genetic diversity and spatiotemporal distributions. This information is crucial for prevention and control of disease spreading at a local and worldwide level. In Costa Rica (CR), the disease was first reported at the beginning of the 20th century and has not been controlled despite many efforts. We characterized 188 B. abortus isolates from CR recovered from cattle, humans and water buffalo, from 2003 to 2018, and whole genome sequencing (WGS) was performed in 95 of them. They were also assessed based on geographic origin, date of introduction, and phylogenetic associations in a worldwide and national context. Our results show circulation of five B. abortus lineages (I to V) in CR, phylogenetically related to isolates from the United States, United Kingdom, and South America. Lineage I was dominant and probably introduced at the end of the 19th century. Lineage II, represented by a single isolate from a water buffalo, clustered with a Colombian sample, and was likely introduced after 1845. Lineages III and IV were likely introduced during the early 2000s. Fourteen isolates from humans were found within the same lineage (lineage I) regardless of their geographic origin within the country. The main CR lineages, introduced more than 100 years ago, are widely spread throughout the country, in contrast to new introductions that seemed to be more geographically restricted. Following the brucellosis prevalence and the farming practices of several middle- and low-income countries, similar scenarios could be found in other regions worldwide.

Interventions to enhance mental health and well-being within high risk industries such as the emergency services have typically focused on individual-level factors, though there is increasing interest in the role of organisational-level interventions. The aim of this study was to examine the importance of different aspects of manager support in determining the mental health of ambulance personnel. A cross-sectional survey was completed by ambulance personnel across two Australian states (N = 1,622). Demographics, manager support and mental health measures were assessed. Hierarchical multiple linear regressions were conducted to determine the explanatory influence of the employee's perception of the priority management places upon mental health issues (manager psychosocial safety climate) and managers' observed behaviours (manager behaviour) on employee common mental disorder and well-being within ambulance personnel. Of the 1,622 participants, 123 (7.6%) were found to be suffering from a likely mental disorder. Manager psychosocial safety climate accounted for a significant amount of the variance in levels of employee common mental health disorder symptoms (13%, p<0.01) and well-being (13%, p<0.01). Manager behaviour had a lesser, but still statistically significant influence upon symptoms of common mental disorder (7% of variance, p<0.01) and well-being (10% of variance, p<0.05). The perceived importance management places on mental health and managers' actual behaviour are related but distinct concepts, and each appears to impact employee mental health. While the overall variance explained by each factor was limited, the fact that each is potentially modifiable makes this finding important and highlights the significance of organisational and team-level interventions to promote employee well-being within emergency services and other high-risk occupations.

PurposeThere is increasing concern regarding the mental health impact of first responder work, with some reports suggesting ambulance personnel may be at particularly high risk. Through this systematic review and meta-analysis we aimed to determine the prevalence of mental health conditions among ambulance personnel worldwide.MethodsA systematic search and screening process was conducted to identify studies for inclusion in the review. To be eligible, studies had to report original quantitative data on the prevalence of at least one of the following mental health outcome(s) of interest (PTSD, depression, anxiety, general psychological distress) for ambulance personnel samples. Quality of the studies was assessed using a validated methodological rating tool. Random effects modelling was used to estimate pooled prevalence, as well as subgroup analyses and meta-regressions for five variables implicated in heterogeneity.ResultsIn total, 941 articles were identified across all sources, with 95 full-text articles screened to confirm eligibility. Of these, 27 studies were included in the systematic review, reporting on a total of 30,878 ambulance personnel. A total of 18 studies provided necessary quantitative information and were retained for entry in the meta-analysis. The results demonstrated estimated prevalence rates of 11% for PTSD, 15% for depression, 15% for anxiety, and 27% for general psychological distress amongst ambulance personnel, with date of data collection a significant influence upon observed heterogeneity.ConclusionAmbulance personnel worldwide have a prevalence of PTSD considerably higher than rates seen in the general population, although there is some evidence that rates of PTSD may have decreased over recent decades.