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Objectives Major trauma centres (MTCs) save lives but rehabilitation to support return-to-work (RTW) is lacking. This paper describes development of a vocational rehabilitation intervention (the ROWTATE intervention) to support RTW following traumatic injury.Design Sequential and iterative person-based approach in four stages—Stage 1: review of evidence about the efficacy and mechanisms of RTW interventions; Stage 2: interviews (n=38) and focus groups (n=25) with trauma survivors and service providers in five UK MTCs to identify the issues, and challenges faced postinjury; Stage 3: codesign workshops (n=43) with trauma stakeholders in MTCs to conceptually test and identify intervention delivery barriers/enablers; Stage 4: meetings (n=7) with intervention development working group (IDWG) to: (1) generate guiding principles, (2) identify key intervention features (process, components, mechanisms) to address unmet rehabilitation needs; (3) generate a logic model and programme theory to illustrate how the intervention works; and (4) develop a training package to support delivery.Results Trauma survivors described unmet needs relating to early advice about RTW; psychological support; pain management; hidden disabilities (eg, fatigue); estimating recovery; and community, amputee and musculoskeletal rehabilitation. Mechanisms of effective interventions identified in the review included early intervention, colocation, employer engagement, case coordination and work accommodations. Intervention features identified by IDWG members (n=13) from stages 1 and 2 were use of stepped-care approaches by occupational therapists (OTs) and clinical psychologists (CPs), OT/CP formulation for complex cases, assessment of mental health problems, individually tailored rehabilitation including vocational goal setting, cross-sector coordination/communication, employer engagement, phased RTW, education/advice for family/employers, exploration of work alternatives, ongoing review of physical and mental health needs, work stability monitoring. Conceptual testing ratified the logic model. Geography and long waiting lists were identified as potential delivery barriers.Conclusions Real-world testing of the intervention is underway in a randomised controlled trial.

BackgroundChildren with craniopharyngiomas (CPs) typically suffer from a life-long chronic disease. The younger the child, the more vulnerable the maturing brain is to invasive therapies such as surgery or radiotherapy. Therefore, treatment modalities facilitating avoidance or delay of invasive therapies are beneficial for these patients. In the last decade, intracystic injection of interferon alfa-2a or alfa-2b evolved as a treatment of choice based on efficacy and minor toxicity. However, the drug is no longer available internationally. After an extensive pharmacological review, peginterferon alfa-2a was identified as the agent with closest similarity.MethodsA retrospective case series is described, including five patients treated with intracystic peginterferon alfa-2a for cystic CP according to an innovative care protocol. After initial CP cyst aspiration, peginterferon alfa-2a was injected once per week via an Ommaya reservoir for 6 weeks followed by response assessment with MRI.ResultsPatients’ age ranged from 4 to 54 years (four patients

Summary: Our objective was to update a clinical practice guideline for the prevention and treatment of Clostridioides difficile infection (CDI) in pediatric patients with cancer and hematopoietic cell transplantation recipients. We reconvened an international multi-disciplinary panel. A systematic review of randomized controlled trials (RCTs) for the prevention or treatment of CDI in any population was updated and identified 31 new RCTs. Strong recommendations were made to use either oral metronidazole or oral vancomycin for non-severe CDI treatment, and to use either oral vancomycin or oral fidaxomicin for severe CDI. A strong recommendation that fecal microbiota transplantation should not be routinely used to treat CDI was also made. The panel made two new good practice statements to follow infection control practices including isolation in patients experiencing CDI, and to minimize systemic antibacterial administration where feasible, especially in patients who have experienced CDI.

The purpose of the current investigation was to develop a pharmaceutical equivalent osmotic drug delivery formulation of Paliperidone (PLD) in the form of controlled porosity osmotic pump tablets (CPOT) in order to keep the drug's steady state concentration in the body. This helps to achieve the greatest therapeutic benefit with the fewest side effects. For the purpose of identifying various formulation attributes, preliminary trials were conducted. Taguchi design was used to study the influence of seven input factors namely drug to polymer ratio, polymer 1(HPMC K100 M) to polymer 2 (HPMC K15 ​M), drug to total osmogens, coating level, amount of pore former, concentration of ethyl cellulose and amount of plasticizer on dependent variable similarity factor (f2). Utilizing the Minitab 17, data analysis was done. The similarity factor (f2) was computed using the osmotic tablet reference product INVEGA®. The findings demonstrate that each of the seven independent variables significantly affects the similarity factor. For optimized batch, both core and coated tablets showed acceptable pharmaco-technical parameters. The release profile of the optimized batch tablets was found to be similar to that of reference product with good zero-order release pattern. Drug release was observed through the channels formed by in-situ pores on tablet surface performed using SEM. From the results it can be concluded that prepared CPOT of PLD was found pharmaceutical equivalent with commercial product which is cost effective and fully compliance with cGMP.

BackgroundMany intensive care unit (ICU) staff experience intrusive memories following work-related traumatic events, which can lead to long-term mental health outcomes and impact work functioning. There is a need for interventions that target intrusive memories in this population; however, factors such as mental health stigma and difficulty in fitting interventions into busy schedules can pose barriers. The Brief Gameplay Intervention For National Health Service Intensive Care Unit Staff Affected By COVID-19 Trauma (GAINS) study tested a brief, digital imagery-competing task intervention (including computer gameplay) with the aim of reducing the recurrence of intrusive memories, which holds promise for overcoming some of these barriers. ObjectiveThis substudy aims to explore barriers and facilitators to the uptake and practical use of the intervention by ICU staff, along with its acceptability, and iteratively explore the impact of intervention optimizations to further refine the intervention. MethodsThe GAINS study is a randomized controlled trial comparing access to a brief digital imagery-competing task intervention for 4 weeks with usual care followed by delayed access to the intervention. The participants were ICU staff who worked during the COVID-19 pandemic and experienced intrusive memories. All participants were sent a questionnaire at 4 weeks to gather data about intervention acceptability. Nested within the randomized controlled trial, a subset of 16 participants was interviewed, and data were analyzed using thematic analysis drawing from a framework approach. ResultsBoth quantitative and qualitative data indicated high acceptability of the intervention. Intervention use data show that, on average, staff were able to target approximately 73% (3.64/4.88) of their intrusive memories and engaged with the Tetris component for the full 20 minutes per session. Overall, on the acceptability questionnaire, staff found the intervention easy to use, helpful, and highly acceptable. The interviews generated four themes: approach to the intervention, positives of the intervention, negatives of the intervention, and improvements and optimizations. Findings highlighted barriers that ICU staff experienced: stigma, feeling weak for seeking help, not wanting colleagues to know they were struggling, and skepticism. However, they provided suggestions on how barriers could be overcome and discussed the advantages of the intervention when compared with other treatments. Although participants described many positive aspects of the intervention, such as being easy to use, enjoyable, and leading to a reduction in the frequency or intensity of intrusive memories, they also raised practical issues for implementation. ConclusionsThe intervention has the potential to overcome stigma and reduce the frequency of intrusive memories after traumatic events among ICU staff. Further refinement is needed to improve the adoption and reach of this intervention. A limitation is that we could not interview the National Health Service staff who were unable or unwilling to take part in the trial.

Few previous studies have considered the experiences of people with long covid returning to work beyond symptoms in terms of employer and other support factors. The aim of this research was to understand the experience of returning to work for those with long covid symptoms in contrast to the non-long covid group who had not experienced COVID-19 during the time restrictions were imposed to limit the spread of COVID-19 infection. Twenty-one participants with long covid and 13 participants who had not had COVID-19 were interviewed. Themes were identified from transcripts using framework analysis. Participants with long covid experienced difficulties returning to work, particularly from fatigue, cognitive symptoms and breathlessness. Symptoms were heterogeneous and fluctuated in severity over time. A lack of understanding from colleagues and managers sometimes led to a premature return to work without adequate support, associated with further long covid relapse. Outside-of-work, support was salient for a successful return to work. The standard phased return offered by employers may be too short and rigid for some people with long covid. They may benefit from a tailored intervention to support a return to work that targets symptom management, and engages with work colleagues, managers, and family members.

Background: Alpha-Stim AID is a device for the treatment of anxiety, insomnia and depression. Evidence on patient experiences of using the device for depressive symptoms is scarce. We explored participant experiences of the device during a randomised controlled trial comparing active versus sham Alpha-Stim AID (Alpha-Stim-D Trial) for the treatment of depressive symptoms in primary care. Methods: Fourteen qualitative semi-structured interviews were conducted via Microsoft Teams or over the telephone six months after recruitment to the trial had finished. Participants reported moderate severity depressive symptoms (mean PHQ-9 score of 15.8), 50% were male and the mean age was 40.0 years (age range 19–65 years). Interviews were analysed using inductive reflexive thematic analysis. Results: Participants’ initial views of the Alpha-Stim AID device was that it was an interesting and novel treatment for depressive symptoms, although some were initially wary that the device may change brain function. Many found the device (active and sham) straightforward to use, portable and easy to incorporate into their life with positive effects on mood, anxiety and sleep. Some experienced difficulties with the battery, ear clips and wires. Additional challenges included the stigma of drawing attention to their need for a mental health treatment, device cost, and experiencing no change or worsening of symptoms. Limitations: The study lacked perspectives from participants who decided not to commence using the Alpha-Stim AID device or complete treatment. Conclusions: People with depressive symptoms were interested in using the Alpha-Stim AID, as it provided an alternative accessible treatment option. Despite experienced barriers, Alpha-Stim AID was perceived favourably by most participants. Participant experience may be enhanced by addressing device impracticalities, but its cost could restrict treatment accessibility.

We report the spillover of highly pathogenic avian influenza A(H5N1) into marine mammals in the northeastern United States, coincident with H5N1 in sympatric wild birds. Our data indicate monitoring both wild coastal birds and marine mammals will be critical to determine pandemic potential of influenza A viruses.

In recent years, due to their distinctive and adaptable therapeutic effects, many natural bioactive compounds have been commonly used to treat diseases. Their limited solubility, low bioavailability, inadequate gastrointestinal tract stability, high metabolic rate, and shorter duration of action limited their pharmaceutical applications. However, those can be improved using nanotechnology to create various drug delivery systems, including lipid-based nanoparticles, to adjust the compounds’ physicochemical properties and pharmacokinetic profile. Because of the enormous technical advancements made in the fundamental sciences and the physical and chemical manipulation of individual atoms and molecules, the subject of nanotechnology has experienced revolutionary growth. By fabricating certain functionalized particles, nanotechnology opens an innovative horizon in research and development for overcoming restrictions, including traditional medication administration systems. Nanotechnology-driven bioactive compounds are certain to have a high impact and clinical value for current and future uses. Lipid-based nanotechnologies were shown to deliver a range of naturally occurring bioactive compounds with decent entrapment potential and stability, a successfully controlled release, increased bioavailability, and intriguing therapeutic activity. This review outlines bioactive compounds such as paclitaxel, curcumin, rhodomyrtone, quercetin, kaempferol, resveratrol, epigallocatechin-3-gallate, silymarin, and oridonin, fortified within either a natural or synthetic lipid-based drug delivery system based on nanotechnology and their evaluation and clinical considerations.

Summary: Objective was to update a clinical practice guideline (CPG) for the management of fatigue in children and adolescents with cancer or pediatric hematopoietic cell transplant recipients. We reconvened a multi-disciplinary and multi-national panel. While the previous 2018 CPG evaluated adult and pediatric randomized controlled trials (RCTs) to manage fatigue, this 2023 update revised previous recommendations based only on pediatric RCTs. Twenty RCTs were included in the updated systematic review. Physical activity significantly reduced fatigue (standardized mean difference −0.44, 95% confidence interval −0.64 to −0.24; n = 8 RCTs). Using the 2018 recommendations as a basis, the panel continued to make strong recommendations to use physical activity, and to offer relaxation, mindfulness or both, to manage fatigue in pediatric patients. Cognitive or cognitive behavioral therapies may be offered. Pharmacological approaches should not be routinely used. The panel made a new good practice statement to routinely assess for fatigue, ideally using a validated scale.

Patients with heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) have increased mortality and increased risk of stroke. Due to the heterogeneous nature of both disease processes, it is difficult to ascertain whether the diagnosis and progression of AF is the cause of deterioration or if it is a symptom of worsening heart failure. This presents physicians with a clinical conundrum of whether optimizing their heart failure will decrease the overall AF burden or if restoration of sinus rhythm is necessary to optimize patients with HFpEF. In this paper, we will review the impact of AF in patients with HFpEF, the pathophysiology and heterogeneity of HFpEF and AF, and the management of these patients. As HFpEF and AF become more prevalent, managing these disease processes needs standardization to improve outcomes. Further research is needed to understand the complex interplay between AF and HFpEF to help determine the best management strategy.

Background: This study assessed the potential cost-effectiveness of high (80–100%) vs low (21–35%) fraction of inspired oxygen (FiO2) at preventing surgical site infections (SSIs) after abdominal surgery in Nigeria, India, and South Africa. Methods: Decision-analytic models were constructed using best available evidence sourced from unbundled data of an ongoing pilot trial assessing the effectiveness of high FiO2, published literature, and a cost survey in Nigeria, India, and South Africa. Effectiveness was measured as percentage of SSIs at 30 days after surgery, a healthcare perspective was adopted, and costs were reported in US dollars ($). Results: High FiO2 may be cost-effective (cheaper and effective). In Nigeria, the average cost for high FiO2 was $216 compared with $222 for low FiO2 leading to a −$6 (95% confidence interval [CI]: −$13 to −$1) difference in costs. In India, the average cost for high FiO2 was $184 compared with $195 for low FiO2 leading to a −$11 (95% CI: −$15 to −$6) difference in costs. In South Africa, the average cost for high FiO2 was $1164 compared with $1257 for low FiO2 leading to a −$93 (95% CI: −$132 to −$65) difference in costs. The high FiO2 arm had few SSIs, 7.33% compared with 8.38% for low FiO2, leading to a −1.05 (95% CI: −1.14 to −0.90) percentage point reduction in SSIs. Conclusion: High FiO2 could be cost-effective at preventing SSIs in the three countries but further data from large clinical trials are required to confirm this.

Diabetes mellitus type 2 is a chronic metabolic condition whose incidence has been continuously growing around the world. As a result of this tendency, it is quickly becoming an epidemic in some parts of the world, with the number of individuals affected anticipated to double in the next decade as the world's population ages, adding to the already existing load on healthcare providers, particularly in poor developing countries. World Health Organization (WHO) guidelines are still used for screening and diagnosis, which include both clinical and laboratory characteristics. There is currently no cure for the disease; however, therapy options include lifestyle changes, obesity management, oral hypoglycemic medications, and insulin sensitizers such as metformin, a biguanide that reduces insulin resistance which is used as first line medication especially for obese patients. The traditional herbal medicine like garlic, neem, bitter gourd, aloe vera, onion, methi, amla, jamun, baheda etc. are also used for the treatment of the diabetes. Other effective medication includes non-sulfonylurea secretagogues, thiazolidinediones, alpha glucoside inhibitors, and insulin. Recent research into the biology of type 2 diabetes has led to the development of new medications such as glucagon-like peptide 1 analogues: dipeptidyl peptidase inhibitors, sodium glucose cotransporter 2 inhibitors, and 11-hydroxysteroid dehydrogenase 1 inhibitors, insulin releasing glucokinase activators. The novel drug delivery improves the treatment of diabetes by the inhaled insulin. Keywords: Type 2 diabetes mellitus, Diabetes complications, Diabetes diagnosis, Diabetes management, Antidiabetic newer drugs, Antidiabetic herbal drugs

Abstract Background Despite the large body of research on the adverse effects of income inequality, to date, few studies have examined its impact on sleep. The objective of this investigation is to examine the association between US state income inequality and the odds for regularly obtaining inadequate (

BackgroundBladder cancer survivors and their caregivers face profound practical (eg, use of stoma appliances and care for urinary diversion methods) and psychosocial (eg, depression and anxiety) challenges after surgical treatment with cystectomy. ObjectiveTo improve the health-related quality of life and postsurgical outcomes of both bladder cancer survivors and their caregivers, the team, in collaboration with Sourcetop, Inc (software design) and Dappersmith (graphic design), developed the Cancer Resource and Information Support (CRIS) software. The purpose of this manuscript is to report on the development and usability testing of the CRIS software. MethodsThe development of the CRIS software was guided by the Obesity-Related Behavioral Intervention Trials (ORBIT) model for developing behavioral treatments for chronic diseases. The ORBIT model is unique in that it proposes a flexible and progressive process with prespecific clinically significant milestones for forward movement and returns to earlier stages for refinement, and it facilitates communication among diverse groups by using terminology from the drug development model. This paper focuses on 2 phases of the ORBIT model: phase IA: define and IB: refine. During phase IA, the study team developed solutions for the stated clinical problem—adjustment to life post cystectomy—by reviewing the literature and collecting feedback from clinicians, professional organizations, bladder cancer survivors, and their caregivers. During Phase IB, the study team focused on tailoring content in the CRIS software to the user as well as usability testing with 7 participants. ResultsThe finished product is CRIS, a web-based software for survivors of bladder cancer and their caregivers to serve as a health management and lifestyle resource after surgery. Overarching themes from phase IA (participant feedback) included how to use new medical equipment, tips and tricks for easier living with new medical equipment, questions about health maintenance, and questions about lifestyle modifications. To accommodate our target population, we also incorporated recommendations from the Americans with Disabilities Act for website design, such as large text size, large paragraph spacing, highly contrasting text and background colors, use of headings and labels to describe the purpose of the content, portrait orientation without the need for horizontal scrolling, multiple ways to access a web page within a set of pages, ability to navigate web pages in sequential order, and in-text links that are descriptive. Usability participants evaluated CRIS very positively, indicating that it was easy to use, the functions were well-integrated, and if available, they would use CRIS frequently. ConclusionsCRIS, developed over the course of 18 months by integrating feedback from experts, literature reviews, and usability testing, is the first web-based software developed for bladder cancer survivors and their caregivers to help them adjust to life following cystectomy. The efficacy of CRIS in improving patients’ and caregivers’ quality of life is currently being evaluated in a randomized controlled trial.

Abstract Background Major depression is the second leading cause of years lost to disability worldwide and is a leading contributor to suicide. However, first-line antidepressants are only fully effective for 33%, and only 40% of those offered psychological treatment attend for two sessions or more. Views gained from patients and primary care professionals are that greater treatment uptake might be achieved if people with depression could be offered alternative and more accessible treatment options. Although there is evidence that the Alpha-Stim Anxiety Insomnia and Depression (AID) device is safe and effective for anxiety and depression symptoms in people with anxiety disorders, there is much less evidence of efficacy in major depression without anxiety. This study investigates the effectiveness of the Alpha-Stim AID device, a cranial electrotherapy stimulation (CES) treatment that people can safely use independently at home. The device provides CES which has been shown to increase alpha oscillatory brain activity, associated with relaxation. Methods The aim of this study is to investigate the clinical and cost-effectiveness of Alpha-Stim AID in treatment-seeking patients (aged 16 years upwards) with moderate to moderately severe depressive symptoms in primary care. The study is a multi-centre parallel-group, double-blind, non-commercial, randomised controlled superiority trial. The primary objective of the study is to examine the clinical efficacy of active daily use of 8 weeks of Alpha-Stim AID versus sham Alpha-Stim AID on depression symptoms at 16 weeks (8 weeks after the end of treatment) in people with moderate severity depression. The primary outcome is the 17-item Hamilton Depression Rating Scale at 16 weeks. All trial and treatment procedures are carried out remotely using videoconferencing, telephone and postal delivery considering the COVID-19 pandemic restrictions. Discussion This study is investigating whether participants using the Alpha-Stim AID device display a reduction in depressive symptoms that can be maintained over 8 weeks post-treatment. The findings will help to determine whether Alpha-Stim AID should be recommended, including being made available in the NHS for patients with depressive symptoms. Trial registration ISRTCN ISRCTN11853110 . Registered on 14 August 2020

Background:. The aim of this study is to compare clinical and radiographic outcomes of open reduction and internal fixation versus closed reduction and percutaneous pinning of metacarpal fractures in relation to anatomic and surgical variables. Methods:. Electronic medical records at two institutions were reviewed for patients who underwent surgical intervention for metacarpal fractures. Data were collected from those who underwent reduction and internal fixation with either plates or Kirschner wires (K-wires). Inclusion criteria included minimum postoperative follow-up of 60 days and age 18 years or older. Exclusion criteria included insufficient radiographic data, previously attempted closed reduction with immobilization, pathologic fracture mechanism, history of previous trauma or surgery to the affected bone, and fixation technique other than plate or K-wire. Results:. We reviewed data for patients treated over a 22-year time period. Ultimately, 81 metacarpal shaft and neck fractures in 60 patients met inclusion criteria. Among all metacarpal fractures, complications were present in 39 (48.1%) cases. There were no significant associations between complication prevalence and hardware type. Revision surgery was required in 11 (13.6%) patients; there were no significant associations between revision procedures and hardware type. Postoperatively, all patients with imaging data had radiograph follow-up to assess union status. There was no significant association between time to union and hardware type. Conclusions:. Outcomes showed no significant difference between plate and pin fixation for metacarpal shaft and neck fractures. These findings suggest that surgeons may have flexibility to decide on the type of operative intervention while considering patient-specific factors, such as the need for early mobilization.

Abstract Background Skin cancers are among the widely prevalent forms of cancer worldwide. The increasing industrialization and accompanied environmental changes have further worsened the skin cancer statistics. The stern topical barrier although difficult to breach is a little compromised in pathologies like skin cancer. The therapeutic management of skin cancers has moved beyond chemotherapy and surgery. Main body of the abstract The quest for a magic bullet still prevails, but topical drug delivery has emerged as a perfect modality for localized self-application with minimal systemic ingress for the management of skin cancers. Advances in topical drug delivery as evidenced by the exploration of nanocarriers and newer technologies like microneedle-assisted/mediated therapeutics have revolutionized the paradigms of topical treatment. The engineered nanovectors have not only been given the liberty to experiment with a wide-array of drug carriers with very distinguishing characteristics but also endowed them with target specificity. The biologicals like nucleic acid-based approaches or skin penetrating peptide vectors are another promising area of skin cancer therapeutics which has demonstrated potential in research studies. In this review, a panoramic view is presented on the etiology, therapeutic options, and emerging drug delivery modalities for skin cancer. Short conclusion Nanocarriers have presented innumerable opportunities for interventions in skin cancer therapeutics. Challenge persists for the bench to bedside translation of these highly potential upcoming therapeutic strategies. Graphic abstract

Abstract Background Drug checking is a harm reduction intervention aiming to reduce substance use-related risks by improving drug user knowledge of the composition of unregulated drugs. With increasing fears of fentanyl adulteration in unregulated drugs, this study sought to examine whether the expected type of drug checked (stimulant vs. opioid) was associated with timing of drug checking service utilization (pre-consumption vs. post-consumption). Methods Data were derived from drug checking sites in British Columbia between October 31, 2017 and December 31, 2019. Pearson’s Chi-square test was used to examine the relationship between expected sample type (stimulant vs. opioid) and timing of service utilization. Odds ratios (OR) were calculated to assess the strength of this relationship. The Mantel–Haenszel (MH) test was used to adjust for service location. Results A total of 3561 unique stimulant and opioid samples were eligible for inclusion, including 691 (19.40%) stimulant samples; and 2222 (62.40%) samples that were tested pre-consumption. Results indicated a positive association between testing stimulant samples and testing pre-consumption (OR = 1.45; 95% CI 1.21–1.73). Regions outside of the epicenter of the province’s drug scene showed a stronger association with testing pre-consumption (ORMH = 2.33; 95% CI 1.51–3.56) than inside the epicenter (ORMH = 1.33; 95% CI 1.09–1.63). Conclusion Stimulant samples were more likely to be checked pre-consumption as compared with opioid samples, and stimulant samples were more likely to be tested pre-consumption in regions outside the epicenter of the province’s drug scene. This pattern may reflect a concern for fentanyl-adulterated stimulant drugs.

Abstract Background Traumatic injuries are common amongst working-age adults. Survivors often experience physical and psychological problems, reduced quality of life and difficulty returning to work. Vocational rehabilitation improves work outcomes for a range of conditions but evidence of effectiveness for those with traumatic injuries is lacking. This study assesses feasibility of delivering a vocational rehabilitation intervention to enhance return to work and improve quality of life and wellbeing in people with at least moderate trauma to inform design of a definitive randomised controlled trial (RCT). Methods Non-randomised, single-arm, multi-centre mixed-methods feasibility study with nested case studies and qualitative study. The case studies comprise interviews, observations of clinical contacts and review of clinical records. The qualitative study comprises interviews and/or focus groups. Participants will be recruited from two UK major trauma centres. Participants will comprise 40 patients aged 16–69 with an injury severity score of > 8 who will receive the intervention and complete questionnaires. Interviews will be conducted with 10 patients and their occupational therapists (OTs), clinical psychologists (CPs), employers and commissioners of rehabilitation services. Fidelity will be assessed in up to six patients by observations of OT and CP—patient contacts, review of patient records and intervention case report forms. OT and CP training will be evaluated using questionnaires and competence to deliver the intervention assessed using a team objective structured clinical examination and written task. Patients participating in and those declining participation in the study will be invited to take part in interviews/focus groups to explore barriers and facilitators to recruitment and retention. Outcomes include recruitment and retention rates, intervention fidelity, OT and CP competence to deliver the intervention, experiences of delivering or receiving the intervention and factors likely to influence definitive trial delivery. Discussion Effective vocational rehabilitation interventions to enhance return to work amongst trauma patients are urgently needed because return to work is often delayed, with detrimental effects on health, financial stability, healthcare resource use and wider society. This protocol describes a feasibility study delivering a complex intervention to enhance return to work in those with at least moderate trauma. Trial registration ISRCTN: 74668529 . Prospectively registered on 23 January 20

The present study aimed to investigate the brain targeting efficacy of Lamotrigine (LTG) loaded PLGA nanoparticles (LTG-PNPs) upon intranasal administration. LTG-PNPs were fabricated through the emulsification-solvent evaporation technique and evaluated for % Entrapment efficiency, particle size, in-vitro release, surface morphology, crystallinity, ex-vivo permeation & thermal behaviour. Biodistribution, gamma scintigraphy, and pharmacodynamic studies were performed in BALB/c mice, New Zealand rabbits, and Wistar rats respectively. LTG-PNPs exhibited % EE 71%; particle size 170.0 nm; Polydispersity index 0.191; zeta potential −16.60 mV. LTG-PNPs exhibited a biphasic release pattern. Biodistribution and gamma scintigraphy studies proved a greater amount of LTG in the brain following intranasal delivery of LTG-PNPs in comparison to LTG-SOL. Pharmacodynamic studies demonstrated delayed seizure onset time with LTG-PNPs in comparison to LTG-SOL. Intranasal administration of LTG-PNPs provided prolonged release, higher bioavailability, and better brain targeting bypassing the BBB. The developed formulation could be administered as a once-a-day formulation that would reduce the dosing frequency; dose; dose-related side effects; cost of the therapy and would be beneficial in the management of epilepsy as compared to the LTG-SOL. However, the proof of concept generated through these studies needs to be further validated in higher animals and human volunteers.

Objectives This study aimed to: (1) understand the context for delivering a trauma vocational rehabilitation (VR) intervention; (2) identify potential barriers and enablers to the implementation of a VR intervention post-trauma.Design Qualitative study. Data were collected in person or via phone using different methods: 38 semistructured interviews, 11 informal ‘walk-through care pathways’ interviews, 5 focus groups (n=25), 5 codesign workshops (n=43). Data were thematically analysed using the framework approach, informed by the Consolidated Framework for Implementation Research.Setting Stakeholders recruited across five UK major trauma networks.Participants A variety of stakeholders were recruited (n=117) including trauma survivors, rehabilitation physicians, therapists, psychologists, trauma coordinators and general practitioners. We recruited 32 service users (trauma survivors or carers) and 85 service providers.Results There were several issues associated with implementing a trauma VR intervention including: culture within healthcare/employing organisations; extent to which healthcare systems were networked with other organisations; poor transition between different organisations; failure to recognise VR as a priority; external policies and funding. Some barriers were typical implementation issues (eg, funding, policies, openness to change). This study further highlighted the challenges associated with implementing a complex intervention like VR (eg, inadequate networking/communication, poor service provision, perceived VR priority). Our intervention was developed to overcome these barriers through adapting a therapist training package, and by providing early contact with patient/employer, a psychological component alongside occupational therapy, case coordination/central point of contact, and support crossing sector boundaries (eg, between health/employment/welfare).Conclusions Findings informed the implementation of our VR intervention within the complex trauma pathway. Although we understand how to embed it within this context, the success of its implementation needs to be measured as part of a process evaluation in a future trial.

Study objective: This study sought to assess the predictive value of H2FPEF score in patients with COVID-19. Design: Retrospective study. Setting: Rush University Medical Center. Participants: A total of 1682 patients had an echocardiogram in the year preceding their COVID-19 admission with a preserved ejection fraction (≥50%). A total of 156 patients met inclusion criteria. Interventions: Patients were divided into H2FPEF into low (0–2), intermediate (3–5), and high (6–9) score H2FPEF groups and outcomes were compared. Main outcome measures: Adjusted multivariable logistic regression models evaluated the association between H2FPEF score group and a composite outcome for severe COVID-19 infection consisting of (1) 60-day mortality or illness requiring (2) intensive care unit, (3) intubation, or (4) non-invasive positive pressure ventilation. Results: High H2FPEF scores were at increased risk for severe COVID-19 infection when compared intermediate to H2FPEF score groups (OR 2.18 [CI: 1.01–4.80]; p = 0.049) and low H2FPEF score groups (OR 2.99 [CI: 1.22–7.61]; p

Silibinin (SB) is shown to have an anticancer properties. However, its clinical therapeutic effects have been restricted due to its low water solubility and poor absorption after oral administration. The aim of this study was to develop SB-loaded PCL/Pluronic F68 nanoparticles for pulmonary delivery in the treatment of lung cancer. A modified solvent displacement process was used to make nanoparticles, which were then lyophilized to make inhalation powder, Nanoparticles were characterized with DSC, FTIR,SEM and In vitro release study. Further, a validated HPLC method was developed to investigate the Biodistribution study, pharmacokinetic parameters. Poly Caprolactone PCL / Pluronic F68 NPs showed the sustained release effect up to 48 h with an emitted (Mass median Aerodynamic diameter)MMAD and (Geometric size distribution)GSD were found to be 4.235 ±0.124 and 1.958±1.23 respectively. More specifically, the SB Loaded PCL/Pluronic F 68 NPs demonstrated long circulation and successful lung tumor-targeting potential due to their cancer-targeting capabilities. SB Loaded PCL/Pluronic F68 NPs significantly inhibited tumour growth in lung cancer-induced rats after inhalable administration. In a pharmacokinetics study, PCL/ Pluronic F68 NPs substantially improved SB bioavailability, with a more than 4-fold rise in AUC when compared to IV administration. These findings indicate that SB-loaded PCL/PluronicF68 nanoparticles may be a successful lung cancer therapy delivery system.

The gastrointestinal flora consists of several microbial strains in variable combinations in both healthy and sick humans. To prevent the risk of the onset of disease and perform normal metabolic and physiological functions with improved immunity, a balance between the host and gastrointestinal flora must be maintained. Disruption of the gut microbiota triggered by various factors causes several health problems, which promote the progression of diseases. Probiotics and fermented foods act as carriers of live environmental microbes and play a vital role in maintaining good health. These foods have a positive effect on the consumer by promoting gastrointestinal flora. Recent research suggests that the intestinal microbiome is important in reducing the risk of the onset of various chronic diseases, including cardiac disease, obesity, inflammatory bowel disease, several cancers, and type 2 diabetes. The review provides an updated knowledge base about the scientific literature addressing how fermented foods influence the consumer microbiome and promote good health with prevention of non-communicable diseases. In addition, the review proves that the consumption of fermented foods affects gastrointestinal flora in the short and long term and can be considered an important part of the diet.

In the first 600 sols of the Mars2020 mission, L _S 5.6 ^o – 316.8 ^o , 46 cloud movies and 145 cloud surveys were collected to observe clouds at Jezero Crater, the landing site of the Perseverance Rover. Cloud movies were processed using the Mean-Frame Subtraction (MFS) method for revealing cloud structures, which were subsequently analyzed using digital-image processing. Two-dimensional Fast Fourier Transforms (2D-FFT) were used to compute cloud structure sizes ranging from 2.90 to 15.25 km for clouds between 30 and 50 km altitude, based on coincident Mars Climate Sounder vertical profiles of atmospheric water-ice. Same-value thresholding was used to detect the cloud structures in MFS-processed and projected cloud movies. The resolution dependence that was needed to resolve these structures over various thresholds was examined to find multifractal scaling of Mars clouds for resolutions between 0.1 and 1.6 km. We characterize the multiscaling observed in the images and its implications for the design of cloud-tracking cameras from the surface as well as for cloud-resolving models.

Background: With more effective treatments and improved outcomes in thalassemia, there is increasing focus on its psychological sequelae. Most published data on this topic are from high-income countries and much less so from low- and middle-income countries, where thalassemia is more prevalent. Aim: The aim of this study was to systematically evaluate the psychiatric morbidity and quality of life in relation to demographic- and illness-related variables among Sri Lankan patients with thalassemia. Methods: This cross-sectional investigation was conducted at the University of Kelaniya Teaching Hospital in Sri Lanka. Patients with all forms of thalassemia, over 12 years of age, and in stable medical condition (n = 120) were recruited. Assessment tools included a general demographic questionnaire, the Beck Depression Inventory-II, and the World Health Organization Quality of Life Measure–Brief. Statistical analysis was conducted using linear regressions, Chi-squares, and analyses of variance. Results: Lack of family support, longer duration of inpatient admission, and female gender were associated with higher depression scores and reduced quality of life. Environmental and social quality of life were positively correlated with levels of peer support in males, while increased support from religion correlated with lower depression scores and higher satisfaction with environmental and psychological quality of life in women. There was no association between the type of thalassemia and either depression or quality of life measures. Conclusion: Several factors may influence the psychological state and well-being of patients with thalassemia in Sri Lanka. Specific service innovations (some gender-specific) may help to address these factors to improve treatment outcome and well-being.

Background: In the coronavirus disease 2019 (COVID-19) global pandemic, patients with cardiovascular disease represent a vulnerable population with higher risk for contracting COVID-19 and worse prognosis with higher case fatality rates. However, the relationship between COVID-19 and heart failure (HF) is unclear, specifically whether HF is an independent risk factor for severe infection or if other accompanying comorbidities are responsible for the increased risk. Methods: This is a retrospective analysis of 1331 adult patients diagnosed with COVID-19 infection between March and June 2020 admitted at Rush University System for Health (RUSH) in metropolitan Chicago, Illinois, USA. Patients with history of HF were identified by International Classification of Disease, Tenth Revision (ICD-10) code assignments extracted from the electronic medical record. Propensity score matching was utilized to control for the numerous confounders, and univariable logistic regression was performed to assess the relationship between HF and 60-day morbidity and mortality outcomes. Results: The propensity score matched cohort consisted of 188 patients in both the HF and no HF groups. HF patients did not have lower 60-day mortality (OR 0.81; p = 0.43) compared to patients without HF. However, those with HF were more likely to require readmission within 60 days (OR 2.88; p

Introduction Surgical site infection (SSI) is one of the most common healthcare-associated infections (HAIs). However, there is a lack of data available about SSI in children worldwide, especially from low-income and middle-income countries. This study aimed to estimate the incidence of SSI in children and associations between SSI and morbidity across human development settings.Methods A multicentre, international, prospective, validated cohort study of children aged under 16 years undergoing clean-contaminated, contaminated or dirty gastrointestinal surgery. Any hospital in the world providing paediatric surgery was eligible to contribute data between January and July 2016. The primary outcome was the incidence of SSI by 30 days. Relationships between explanatory variables and SSI were examined using multilevel logistic regression. Countries were stratified into high development, middle development and low development groups using the United Nations Human Development Index (HDI).Results Of 1159 children across 181 hospitals in 51 countries, 523 (45·1%) children were from high HDI, 397 (34·2%) from middle HDI and 239 (20·6%) from low HDI countries. The 30-day SSI rate was 6.3% (33/523) in high HDI, 12·8% (51/397) in middle HDI and 24·7% (59/239) in low HDI countries. SSI was associated with higher incidence of 30-day mortality, intervention, organ-space infection and other HAIs, with the highest rates seen in low HDI countries. Median length of stay in patients who had an SSI was longer (7.0 days), compared with 3.0 days in patients who did not have an SSI. Use of laparoscopy was associated with significantly lower SSI rates, even after accounting for HDI.Conclusion The odds of SSI in children is nearly four times greater in low HDI compared with high HDI countries. Policies to reduce SSI should be prioritised as part of the wider global agenda.

Children with movement impairments needing assistive devices for activities of daily living often require novel methods for controlling these devices. Body-machine interfaces, which rely on body movements, are particularly well-suited for children as they are non-invasive and have high signal-to-noise ratios. Here, we examined the use of a head-joystick to enable a child with congenital absence of all four limbs to control a seven degree-of-freedom robotic arm. Head movements were measured with a wireless inertial measurement unit and used to control a robotic arm to perform two functional tasks-a drinking task and a block stacking task. The child practiced these tasks over multiple sessions; a control participant performed the same tasks with a manual joystick. Our results showed that the child was able to successfully perform both tasks, with movement times decreasing by ~40-50% over 6-8 sessions of training. The child's performance with the head-joystick was also comparable to the control participant using a manual joystick. These results demonstrate the potential of using head movements for the control of high degree-of-freedom tasks in children with limited movement repertoire.

Voriconazole is second-generation triazole used for the treatment of fungal infections but has serious unwanted adverse effects, which could be reduced by topical semisolid dosage form. Major drawbacks of topical semisolid products are poor patient compliance, cross contamination; gels are easily rubbed off by clothing and during day-to-day activities, physical instability. The purpose of the present work was to fabricate 0.5% w/w voriconazole transdermal spray for fungal infection. The transdermal spray was generated by using a film forming polymers like Eudragit RLPO and ethyl cellulose (1:2 ratios) along with eutectic camphor: menthol (1:1) mixture used as a penetration enhancer. The formulation optimized by constrained 32 factorial design. Regression analysis and response surface methodology were used to optimize the effect of polymers and formulate checkpoint batch based on overlay plots. The transdermal spray was subjected to evaluate parameters related to formulation and containers. The concentration of Eudragit RLPO and ethyl cellulose was showed influence on viscosity as well as t50. Diffusion study was showed 75% of voriconazole transport with 65.8 μgcm−2 h−1 fluxes. Penetration enhancers’ had shown an increase in 1.68 fold of the penetration of voriconazole through the formulation. The study was concluded that fabricated film forming voriconazole transdermal spray formulations penetrate to the deep layer of the skin and was feasible to treat the dermatological fungal infection. This delivery platform is opened a wide range of treatment of fungal infection as compared to conventional formulations.

Tumor cells activate the G2/M cell cycle checkpoint in response to ionizing radiation (IR) and effector immune cell-derived granzyme B to facilitate repair and survival. Wee1 kinase inhibition reverses the ability of tumor cells to pause at G2/M. Here, we hypothesized that AZD1775, a small molecule inhibitor of Wee1 kinase, could sensitize tumor cells to IR and T-lymphocyte killing and improve responses to combination IR and programmed death (PD)-axis immune checkpoint blockade (ICB). Multiple models of head and neck carcinoma, lung carcinoma and melanoma were used in vitro and in vivo to explore this hypothesis. AZD1775 reversed G2/M cell cycle checkpoint activation following IR, inducing cell death. Combination IR and AZD1775 induced accumulation of DNA damage in M-phase cells and was rescued with nucleoside supplementation, indicating mitotic catastrophe. Combination treatment enhanced control of syngeneic MOC1 tumors in vivo, and on-target effects of systemic AZD1775 could be localized with targeted IR. Combination treatment enhanced granzyme B-dependent T-lymphocyte killing through reversal of additive G2/M cell cycle block induced by IR and granzyme B. Combination IR and AZ1775-enhanced CD8+ cell-dependent MOC1 tumor growth control and rate of complete rejection of established tumors in the setting of PD-axis ICB. Functional assays demonstrated increased tumor antigen-specific immune responses in sorted T-lymphocytes. The combination of IR and AZD1775 not only lead to enhanced tumor-specific cytotoxicity, it also enhanced susceptibility to T-lymphocyte killing and responses to PD-axis ICB. These data provide the pre-clinical rationale for the combination of these therapies in the clinical trial setting.

Sepsis is a severe systemic inflammatory response to infection that manifests with widespread inflammation as well as endothelial and coagulation dysfunction that may lead to hypotension, organ failure, shock, and death. Disseminated intravascular coagulation (DIC) is a complication of sepsis involving systemic activation of the fibrinolytic and coagulation pathways that can lead to multi-organ dysfunction, thrombosis, and bleeding, with a 2-fold increase in mortality. This study demonstrates the diagnostic and prognostic value of profiling various biomarkers of inflammation and infection in patients with sepsis-associated DIC to assess the severity of illness. Deidentified samples were obtained from adult patients with sepsis and suspected DIC. Platelet count, prothrombin time, D-dimer, and fibrinogen levels were used to assign International Society of Thrombosis and Hemostasis DIC scores to plasma samples from 103 patients with sepsis and suspected DIC. Using commercially available enzyme-linked immunosorbent assay, chromogenic assay, and RANDOX Biochip methods, levels of procalcitonin (PCT), extracellular nucleosomes, interleukin (IL) 6, IL-8, IL-10, and tumor necrosis factor α (TNFα) were measured in patients with sepsis and DIC and compared to levels in healthy individuals. Elevated levels of PCT, IL-6, IL-8, IL-10, and TNFα were observed in most patients with sepsis and DIC. Additionally, the levels of these markers show significant positive correlations with each other and with DIC score. Currently, no single biomarker can effectively diagnose DIC in patients with sepsis. This study lays the groundwork for the development of a diagnostic algorithm using several markers of inflammation and infection and DIC score as parameters in assessing severity of sepsis-associated coagulopathy in a clinical setting.

Despite much effort, the bacterial cell cycle has proved difficult to study and understand. Bacteria do not conform to the standard eukaryotic model of sequential cell-cycle phases. Instead, for example, bacteria overlap their phases of chromosome replication and chromosome partitioning. In “eukaryotic terms,” bacteria simultaneously perform “S-phase” and “mitosis” whose coordination is absolutely required for rapid growth and survival. In this review, we focus on the signaling “crosstalk,” meaning the signaling mechanisms that advantageously commit bacteria to start both chromosome replication and chromosome partitioning. After briefly reviewing the molecular mechanisms of replication and partitioning, we highlight the crosstalk research from Bacillus subtilis, Vibrio cholerae, and Caulobacter crescentus. As the initiator of chromosome replication, DnaA also mediates crosstalk in each of these model bacteria but not always in the same way. We next focus on the C. crescentus cell cycle and describe how it is revealing novel crosstalk mechanisms. Recent experiments show that the novel nucleoid associated protein GapR has a special role(s) in starting and separating the replicating chromosomes, so that upon asymmetric cell division, the new chromosomes acquire different fates in C. crescentus’s distinct replicating and non-replicating cell types. The C. crescentus PopZ protein forms a special cell-pole organizing matrix that anchors the chromosomes through their centromere-like DNA sequences near the origin of replication. We also describe how PopZ anchors and interacts with several key cell-cycle regulators, thereby providing an organized subcellular environment for more novel crosstalk mechanisms.

Variability in neonatal clinical practice is well recognized. Respiratory management involves interdisciplinary care and often is protocol driven. The most recent published guidelines for management of respiratory distress syndrome and surfactant administration were published in 2014 and may not reflect current clinical practice in the United States. The goal of this project was to better understand variability in surfactant administration through conduct of health care provider (HCP) interviews. Questions focused on known practice variations included: use of premedication, decisions to treat, technique of surfactant administration and use of guidelines. Data were analyzed for trends and results were communicated with participants. A total of 54 HCPs participated from June to September 2020. In almost all settings, neonatologists or nurse practitioners intubated the infant and respiratory therapists administered surfactant. The INSURE (INtubation-SURrfactant-Extubation) technique was practiced by 83% of participants. Premedication prior to intubation was used by 76% of HCPs. An FiO2 ≥ 30% was the most common threshold for surfactant administration (48%). In conclusion, clinical practice variations exist in respiratory management and surfactant administration and do not seem to be specific to NICU level or institution type. It is unknown what effects the variability in clinical practice might have on clinical outcomes.

Abstract Obesity and its accompanying metabolic syndrome are strongly associated with heightened morbidity and mortality in older adults. In our review of more than 20 epidemiologic studies of major infectious diseases, including tuberculosis, community-acquired pneumonia and sepsis, obesity was associated with better outcomes. A cause-and-effect relationship between over-nutrition and survival with infection is suggested by the results of two preliminary studies of infections in mice, where high-fat feeding for 8–10 wks provided much better outcomes. These better outcomes are reminiscent of many recent studies of “sterile” noninfectious medical and surgical conditions where outcomes for obese patients were better than for their thinner counterparts; this was given the tag “obesity paradox.” Turning to the history of medicine and biological evolution, we hypothesize that metabolic syndrome has ancient origins and is part of a lifelong metabolic program. While that part of the program promotes morbidity and mortality with aging, it helps infants and children as well as adults fight infections and recover from injuries, key events in the centuries before the public health advances of the 20th century. We conclude with speculation on how an understanding of the biological elements that protect obese patients with infections or injuries might be applied advantageously to thin patients with the same medical challenges.

Manual exploratory behaviors during object interaction that form the basis of tool use behavior, are mostly qualitatively characterized in terms of their frequency and duration of occurrence. To fully understand their functional and clinical significance, quantitative movement characterization is needed alongside their qualitative analysis. However, there are two challenges in quantifying them--(a) reliably classifying the type of movement and (b) performing this classification on a time series automatically. Here, we propose a machine learning-based classification method to address these challenges. We measured three common exploratory behaviors (object rotation, fingering, and throwing) in college-aged adults using "sensorized objects" that had wireless Inertial Measurement Units embedded in them. We then calculated several statistical features based on linear acceleration and angular velocity data to train machine learning classifiers to identify these behaviors. All classifiers identified the behaviors with a substantially higher accuracy (average accuracy = 84.95 ± 4.16%) than chance level (33.33%). Of all models tested, Support Vector Machine Quadratic, Support Vector Machine Medium Gaussian, and Narrow Neural Network were the best models in classifying the three behaviors (average accuracy = 89.34 ± 0.12%). This classification method shows potential for automating movement characterization of exploratory behaviors, thereby may aid early assessment of neurodevelopmental disorders.

Head and neck squamous cell carcinomas (HNSCCs) frequently harbor genomic mutations in cell death pathways. Nearly 30% of HNSCCs overexpress Fas-Associated Death Domain (FADD), with or without BIRC2/3 genes encoding cellular Inhibitor of Apoptosis Proteins 1/2 (cIAP1/2), critical components of the Tumor Necrosis Factor (TNF) Receptor signaling pathways. ASTX660 is a novel non-peptidomimetic antagonist of cIAP1/2 and XIAP under evaluation in a clinical trial for advanced solid tumors and lymphomas. Herein, we show that ASTX660, at nanomolar concentrations, sensitized Murine Oral Cancer (MOC1) cells to TNFα. Using syngeneic mouse models, ASTX660 showed additive anti-tumor activity with radiation therapy (XRT), cisplatin chemotherapy, and PD-1 blockade to significantly delay or eradicate MOC1 tumors. These combinations significantly increased CD8 + T cells and dendritic cells, as well as T cell activity. ASTX660 stimulated cytotoxic T lymphocyte (CTL) killing of MOC1 cells expressing ovalbumin. Early stages of CTL killing were predominantly mediated by perforin/granzyme B, whereas later stages were mediated by death ligands TNFα, TRAIL, and FasL. Correspondingly, depletion of CD8 + T cells and NK cells in vivo revealed both types of immune cells to be important components of the complete anti-tumor response enhanced by ASTX660+XRT. These findings serve to inform future studies of IAP inhibitors and support the potential for future clinical trials investigating ASTX660 with XRT and immunotherapies like PD-1/PD-L1 blockade in HNSCC.

Background: Given the lack of clear indications for the use of warfarin in the treatment of atrial fibrillation (AF) in patients on hemodialysis and the potential risks that accompany warfarin use in these patients, we systematically reviewed stroke and bleeding outcomes in hemodialysis patients treated with warfarin for AF. Objective: To systematically review the stroke and bleeding outcomes associated with warfarin use in the hemodialysis population to treat AF. Design: Systematic review. Setting: All adult hemodialysis patients. Patients: Patients on hemodialysis receiving warfarin for the management of AF. Measurements: Any type of stroke and/or bleeding outcomes. Methods: MEDLINE(R) In-Process & Other Non-Indexed Citations and MEDLINE(R) via OVID (1946 to January 11, 2017), and EMBASE via OVID (1974 to January 11, 2017) were searched for relevant literature. Inclusion criteria were randomized controlled trials, observational studies, and case series in English that examined stroke and bleeding outcomes in adult population of patients (over 18 years old) who are on hemodialysis and taking warfarin for AF. Studies with less than 10 subjects, case reports, review articles, and editorials were excluded. Quality of selected articles was assessed using Newcastle-Ottawa Scale (NOS). Results: Of the 2340 titles and abstracts screened, 7 met the inclusion criteria. Two studies showed an association between warfarin use and an increased risk of stroke (Hazard Ratio: 1.93-3.36) but no association with an increased risk of bleed (HR: 0.85-1.04), while 4 studies showed no association between warfarin and stroke outcomes (HR: 0.12-1.17) but identified an association between warfarin and increased bleeding outcome (HR: 1.41-3.96). And 1 study reported neither beneficial nor harmful effects associated with warfarin use. Limitations: The major limitation to this review is that the 7 included studies were observational cohort studies, and thus the outcome measures were not specified and predetermined in a research protocol. Conclusion: Our systematic review demonstrated that for patients with AF who are on hemodialysis, warfarin was not associated with reduced outcomes of stroke but was rather associated with increased bleeding events.

Parkinson's disease (PD) is the second most common neurodegenerative disorder producing a variety of motor and cognitive deficits with the causes remaining largely unknown. The gradual loss of the nigrostriatal pathway is currently considered the pivotal pathological event. To better understand the progression of PD and improve treatment management, defining the disease on a structural basis and expanding brain analysis to extra-nigral structures is indispensable. The anatomical complexity and the presence of neuromelanin, make the use of non-human primates an essential element in developing putative imaging biomarkers of PD. To this end, ex vivo T2-weighted magnetic resonance images were acquired from control and 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets. Volume measurements of the caudate, putamen, and substantia nigra indicated significant atrophy and cortical thinning. Tensor-based morphometry provided a more extensive and hypothesis free assessment of widespread changes caused by the toxin insult to the brain, especially highlighting regional cortical atrophy. The results highlight the importance of developing imaging biomarkers of PD in non-human primate models considering their distinct neuroanatomy. It is essential to further develop these biomarkers in vivo to provide non-invasive tools to detect pre-symptomatic PD and to monitor potential disease altering therapeutics.

BACKGROUND:Investigation of CF800, a novel PEGylated nano-liposomal imaging agent containing indocyanine green (ICG) and iohexol, for real-time near infrared (NIR) fluorescence and computed tomography (CT) image-guided surgery in an orthotopic lung cancer model in nude mice. METHODS:CF800 was intravenously administered into 13 mice bearing the H460 orthotopic human lung cancer. At 48 h post-injection (peak imaging agent accumulation time point), ex vivo NIR and CT imaging was performed. A clinical NIR imaging system (SPY®, Novadaq) was used to measure fluorescence intensity of tumor and lung. Tumor-to-background-ratios (TBR) were calculated in inflated and deflated states. The mean Hounsfield unit (HU) of lung tumor was quantified using the CT data set and a semi-automated threshold-based method. Histological evaluation using H&E, the macrophage marker F4/80 and the endothelial cell marker CD31, was performed, and compared to the liposomal fluorescence signal obtained from adjacent tissue sections. RESULTS:The fluorescence TBR measured when the lung is in the inflated state (2.0 ± 0.58) was significantly greater than in the deflated state (1.42 ± 0.380 (n = 7, p

Objective: To analyze differences in demographic pattern and hospitalization outcomes in post-traumatic stress disorder (PTSD) with opioid use disorder (OUD) patients managed with versus without behavioral therapy (BT). Methods: We conducted case-control study using Nationwide Inpatient Sample and identified PTSD and OUD using ICD–9–CM codes. Linear regression model was used to evaluate impact of BT on inpatient stay and cost. Results: We analyzed 1531 inpatient admissions and 786 patients received BT. Females had higher odds of receiving BT during inpatient management for PTSD with OUD (OR 1.210; 95% CI 1.020–1.436). About 63.1% patients receiving BT were benefited by Medicaid. Patients receiving BT had an increase in hospital stay by 1.27 days (P = 0.085) and hospitalization cost by $4734 (P = 0.018). There were no transfers to short term hospitals and lower transfers to skilled nursing facility (3.8% vs. 10.1%) in patients receiving BT. Conclusion: This study aims to reinforce combination management with psychotropic medications and BT in PTSD patients with comorbid OUD during hospitalization as it significantly decreases adverse disposition of the patient and thereby improves the quality of life post-treatment.

Low back pain is the most common musculoskeletal problem and the single most common cause of disability, often attributed to degeneration of the intervertebral disc. Lack of effective treatment is directly related to our limited understanding of the pathways responsible for maintaining disc health. While transcriptional analysis has permitted initial insights into the biology of the intervertebral disc, complete proteomic characterization is required. We therefore employed liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) protein/peptide separation and mass spectrometric analyses to characterize the protein content of intervertebral discs from skeletally mature wild-type mice. A total of 1360 proteins were identified and categorized using PANTHER. Identified proteins were primarily intracellular/plasma membrane (35%), organelle (30%), macromolecular complex (10%), extracellular region (9%). Molecular function categorization resulted in three distinct categories: catalytic activity (33%), binding (molecule interactions) (29%), and structural activity (13%). To validate our list, we confirmed the presence of 14 of 20 previously identified IVD-associated markers, including matrix proteins, transcriptional regulators, and secreted proteins. Immunohistochemical analysis confirmed distinct localization patterns of select protein with the intervertebral disc. Characterization of the protein composition of healthy intervertebral disc tissue is an important first step in identifying cellular processes and pathways disrupted during aging or disease progression.

Dendritic cells (DCs) play an important role in the generation of anti-cancer immune responses, however there is evidence that DCs in cancer patients are dysfunctional. Lipid accumulation driven by tumor-derived factors has recently been shown to contribute to DC dysfunction in several human cancers, but has not yet been examined in mesothelioma. This study investigated if mesothelioma tumor cells and/or their secreted factors promote increases in DC lipid content and modulate DC function. Human monocyte-derived DCs (MoDCs) were exposed to human mesothelioma tumor cells and tumor-derived factors in the presence or absence of lipoproteins. The data showed that immature MoDCs exposed to mesothelioma cells or factors contained increased lipid levels relative to control DCs. Lipid accumulation was associated with reduced antigen processing ability (measured using a DQ OVA assay), upregulation of the co-stimulatory molecule, CD86, and production of the tolerogenic cytokine, IL-10. Increases in DC lipid content were further enhanced by co-exposure to mesothelioma-derived factors and triglyceride-rich lipoproteins, but not low-density lipoproteins. In vivo studies using a murine mesothelioma model showed that the lipid content of tumor-infiltrating CD4+ CD8α- DCs, CD4- CD8α- DCs DCs and plasmacytoid DCs increased with tumor progression. Moreover, increasing tumor burden was associated with reduced proliferation of tumor-antigen-specific CD8+ T cells in tumor-draining lymph nodes. This study shows that mesothelioma promotes DC lipid acquisition, which is associated with altered activation status and reduced capacity to process and present antigens, which may impair the ability of DCs to generate effective anti mesothelioma T cell responses.

The tumour microenvironment is complex and composed of many different constituents, including matricellular proteins such as connective tissue growth factor (CCN2), and is characterized by gradients in oxygen levels. In various cancers, hypoxia and CCN2 promote stem and progenitor cell properties, and regulate the proliferation, migration and phenotype of cancer cells. Our study was aimed at investigating the effects of hypoxia and CCN2 on chordoma cells, using the human U-CH1 cell line. We demonstrate that under basal conditions, U-CH1 cells express multiple CCN family members including CCN1, CCN2, CCN3 and CCN5. Culture of U-CH1 cells in either hypoxia or in the presence of recombinant CCN2 peptide promoted progenitor cell-like characteristics specific to the notochordal tissue of origin. Specifically, hypoxia induced the most robust increase in progenitor-like characteristics in U-CH1 cells, including increased expression of the notochord-associated markers T, CD24, FOXA1, ACAN and CA12, increased cell growth and tumour-sphere formation, and a decrease in the percentage of vacuolated cells present in the heterogeneous population. Interestingly, the effects of recombinant CCN2 peptide on U-CH1 cells were more pronounced under normoxia than hypoxia, promoting increased expression of CCN1, CCN2, CCN3 and CCN5, the notochord-associated markers SOX5, SOX6, T, CD24, and FOXA1 as well as increased tumour-sphere formation. Overall, this study highlights the importance of multiple factors within the tumour microenvironment and how hypoxia and CCN2 may regulate human chordoma cell behaviour.