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Vascular disorders frequently have differing clinical presentations among women and men. Sex differences exist in vascular access for hemodialysis; women have reduced rates of arteriovenous fistula (AVF) maturation as well as fistula utilization compared with men. Inflammation is increasingly implicated in both clinical studies and animal models as a potent mechanism driving AVF maturation, especially in vessel dilation and wall thickening, that allows venous remodeling to the fistula environment to support hemodialysis. Sex differences have long been recognized in arterial remodeling and diseases, with men having increased cardiovascular events compared with pre-menopausal women. Many of these arterial diseases are driven by inflammation that is similar to the inflammation during AVF maturation. Improved understanding of sex differences in inflammation during vascular remodeling may suggest sex-specific vascular therapies to improve AVF success.

Purpose: We examined long-term clinical outcomes among patients with synchronous oligometastatic non-small cell lung cancer (NSCLC) treated at our institution with definitive thoracic chemoradiation therapy (CRT) and local therapy to all oligometastatic lesions. Methods and Materials: A retrospective review identified 38 patients with synchronous oligometastatic NSCLC (≤3 metastatic lesions) who were treated with definitive CRT to the primary tumor and regional lymph nodes between 1999 and 2017 at our institution. Of the 38 patients, 27 patients (71%) received induction chemotherapy, all of whom responded or stabilized with initial systemic therapy before consideration of CRT. Most patients received chemotherapy concurrently with radiation therapy (n = 32; 84%) and local therapy to the metastatic disease site(s) (n = 34; 89%). We assessed patterns of progression or failure, overall survival (OS), progression-free survival (PFS), and toxicities. Results: The median follow-up duration was 54.9 months. Most patients (84%) presented with N2 to N3 disease. The brain or central nervous system was the most common site of disease progression and occurred in 16 of 28 patients (57%) experiencing any progression and 10 of 16 patients (63%) who initially presented with brain oligometastases. Median OS was 21.1 months (95% confidence interval [CI], 15.6-49.0 months), and median PFS 9.7 months (95% CI, 8.2-14.4 months). The 1-, 2-, and 4-year OS rates were 75.7%, 45.0%, and 33.7%, respectively. On multivariate analysis, both locoregional progression (hazard ratio: 5.8; 95% CI, 2.2-15.0; P = .0003) and distant progression (hazard ratio: 6.0; 95% CI, 2.3-15.4; P = .0002), when treated as time-dependent covariates, were associated with inferior OS. Grade ≥3 esophagitis occurred in 9% and grade ≥3 pneumonitis in 5% of patients with evaluable data. Conclusions: Patients with synchronous oligometastatic NSCLC and a high regional nodal burden treated with definitive thoracic CRT experienced favorable survival outcomes and low toxicity. At our institution, treating oligometastatic disease with CRT after systemic therapy is incorporated into the treatment plan from the onset of therapy, and we monitor the neuraxis closely for progression during and after treatment. Future research should focus on novel treatment combinations, such as immunotherapy or targeted systemic therapy as appropriate to further improve tumor control and survival.

Background and Aim: Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) gene, which confers a limited response to standard-of-care treatment with temozolomide (TMZ), resulting in a lower survival. Dianhydrogalactitol (VAL-083) is a novel bi-functional DNA-targeting agent that induces interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated repair of the O6 guanine alkylator TMZ. A Phase 2 study has been initiated for VAL-083 in newly diagnosed MGMT unmethylated GBM. Subjects and Methods: The study has two parts: part 1 is a dose–escalation and induction format to enroll up to ten patients in which they received VAL-083 at 20, 30, or 40 mg/m2 per day for 3 days every 21 days concurrently with standard radiation treatment and VAL-083 for up to eight additional cycles. Part 2 comprises an expansion phase to enroll up to twenty additional patients. This study was performed with approval by the Institutional Review Board of Sun Yat-sen University Cancer Center (B2016-058-01) on January 13, 2017, and registered with the ClinicalTrials.gov (NCT03050736) on February 13, 2017. Results: After completion of dose escalation, VAL-083, 30 mg/m2 per day, in combination with radiation therapy, was generally safe and well tolerated. At the cutoff date, 23 patients had been enrolled, 14 of whom had been treated in the expansion phase. Consistent with prior studies, myelosuppression was the most common adverse event. Pharmacokinetic assessment indicated that the levels of VAL-083 were as high in the cerebrospinal fluid as in plasma, 2 h postinfusion. Of the 22 patients who had reached their four precycle magnetic resonance imaging assessments, 12 were assessed with disease progression, with a median progression-free survival of 9.9 (95% confidence interval 7.3–12.0) months for all the patients studied. Conclusion: These preliminary data support VAL-083 as a potentially valuable treatment option for newly diagnosed GBM.

Introduction: Resistance exercises and dietary protein have been shown to reverse frailty, yet they are not commonly offered in clinical practice. We aim to measure changes in health outcomes, including physical frailty status (SHARE-FI), clinical frailty status (CFS) and muscle mass, as a result of an optimised exercise and dietary intervention versus usual care in a primary care (PC) setting. The intervention has been derived from our systematic review and meta-analysis findings and optimised through patient and public involvement and multidisciplinary team input. Methods: This study is a multicentre randomised controlled parallel arm trial with a three month follow up. 210 eligible people aged 65 and over, no more than mildly frail, will be recruited in seven PC practices in Ireland and randomly assigned to ‘intervention’ or ‘usual care’. Intervention participants will be provided a leaflet with strength exercises, protein dietary guidance and educational discussion. Baseline measurements will include demographics, health indicators, comorbidities, malnutrition universal screening tool (MUST), frailty status (SHARE-FI, CFS) and muscle mass (bioelectrical impedance). Primary outcome will be frailty status measured by SHARE-FI at three months. Secondary outcomes include CFS, muscle mass, in-patient hospitalisation, long term care admission, and subjective ease of intervention and difference to general health. Statistical analysis will be undertaken by an independent statistician. Discussion: The diversity of tested frailty interventions and lack of clear guidance may contribute to low implementation rates. The REFEREE trial focusses on an optimised intervention for a syndrome that poses growing individual and societal challenges. It is hoped results can encourage mainstream adoption of interventions to reverse clinical frailty and build resilience in primary care. Trial registration: ClinicalTrials.gov ID NCT04628754; registered on 13 November 2020.

Background: Globally, professional firefighters are often exposed to traumatic events and are at high risk of developing posttraumatic stress disorder (PTSD) symptoms. Objective: With the publication of the 11th edition of the International Classification of Diseases (ICD-11) there arose a need for research based on the new diagnostic criteria, and the associated disorder, Complex PTSD (CPTSD). Method: Participants were 1300 former or present firefighters from the UK. Prevalence rates of PTSD and CPTSD were estimated using International Trauma Questionnaire in accordance with ICD-11 criteria, and service related and personal trauma exposure were also assessed using an anonymous online questionnaire. Multinomial logistic regression was performed to assess how service and personal trauma exposure predicted PTSD and CPTSD. Results: CPTSD criteria were met by 18.23% (95% CI 16.13–20.33%) and PTSD criteria were met by 5.62% (95% CI 4.37–6.87%) of the sample. Experiencing higher levels of service-related trauma significantly increased the risk for both PTSD and CPTSD, and nonwork related trauma uniquely predicted CPTSD but not PTSD. Conclusions: This study provided the first examination of the new ICD-11 criteria for PTSD and CPTSD in a large sample of firefighters, and CPTSD was more common than PTSD. Exposure to multiple different types of trauma increased the odds of PTSD and CPTSD.

Background: Firefighters often do not avail of psychological support services within fire services. Hence, investigating help-seeking behaviour is crucial to determine viable support options. Objective: This study attempted to characterize help-seeking behaviour among UK firefighters by profiling and identifying patterns of help-seeking. Methods: An online survey was administered to 1282 UK firefighters who were asked which help-seeking options they availed of within and outside professional settings. The analysis was conducted in two linked phases. First, latent class analysis was used to identify the fewest profiles that most accurately described help-seeking behaviour. Second, multinomial logistic regression analysis was employed to describe class composition using demographic and years in service variables, while ANOVA was employed to identify variation in alcohol consumption and openness to discussing emotions across help-seeking classes. Results: Five distinct help-seeking classes were identified. Class 1 (9.2%) represented firefighters who availed of all forms of support. Class 2, the smallest class (6.9%) represented firefighters who independently sought External Professional Psychological Support. Class 3 (12.2%) represented those who mainly sought Friends Support. Class 4, the largest class (48.7%) represented those who mainly sought Spousal Support. Class 5 (23%) represented firefighters who sought all avenues of Social Support. Regression analyses indicated that the External Psychological Support class was more likely to be single with fewer years in service. Firefighters longest in service were less likely to seek Social Support, and those who relied on Spousal support had the lowest alcohol consumption. Conclusion: Variations in help-seeking behaviour among UK firefighters were found. Firefighters who sought spousal support had the lowest alcohol consumption rates, indicating a protected profile. Firefighters who only sought friends and informal colleagues’ support had the highest alcohol consumption rates and the most difficulty in discussing feelings, indicating a potential at-risk profile. Recognizing these differences in help-seeking patterns is important for targeting interventions.

Background: Medical internship is the final year of training before independent practice for most doctors in Botswana. Internship training in Botswana faces challenges including variability in participants’ level of knowledge and skill related to their completion of medical school in a variety of settings (both foreign and domestic), lack of planned curricular content, and limited time for structured educational activities. Data on trainees’ opinions regarding the content and delivery of graduate medical education in settings like Botswana are limited, which makes it difficult to revise programs in a learner-centered way. Objective: To understand the perceptions and experiences of a group of medical interns in Botswana, in order to inform a large curriculum initiative. Methods: We conducted a targeted needs assessment using structured interviews at one district hospital. The interview script included demographic, quantitative, and free- response questions. Fourteen interns were asked their opinions about the content and format of structured educational activities, and provided feedback on the preferred characteristics of a new curriculum. Descriptive statistics were calculated. Findings: In the current curriculum, training workshops were the highest-scored teaching format, although most interns preferred lectures overall. Specialists were rated as the most useful teachers, and other interns and medical officers were rated as average. Interns felt they had adequate exposure to content such as HIV and tuberculosis, but inadequate exposure to areas including medical emergencies, non-communicable diseases, pain management, procedural skills, X-ray and EKG interpretation, disclosing medical information, and identifying career goals. For the new curriculum, interns preferred a structured case discussion format, and a focus on clinical reasoning and procedural skills. Conclusions: This needs assessment identified several foci for development, including a shift toward interactive sessions focused on skill development, the need to empower interns and medical officers to improve teaching skills, and the value of shifting curricular content to mirror the epidemiologic transition occurring in Botswana. Interns’ input is being used to initiate a large curriculum intervention that will be piloted and scaled nationally over the next several years. Our results underscore the value of seeking the opinion of trainees, both to aid educators in building programs that serve them and in empowering them to direct their education toward their needs and goals.

Induced pluripotent stem cells (iPSC) represent an innovative, somatic cell-derived, easily obtained and renewable stem cell source without considerable ethical issues. iPSC and their derived cells may have enhanced therapeutic and translational potential compared with other stem cells. We previously showed that human iPSC-derived smooth muscle cells (hiPSC-SMC) promote angiogenesis and wound healing. Accordingly, we hypothesized that hiPSC-SMC may be a novel treatment for human patients with chronic limb-threatening ischemia who have no standard options for therapy. We determined the angiogenic potential of hiPSC-SMC in a murine hindlimb ischemia model. hiPSC-SMC were injected intramuscularly into nude mice after creation of hindlimb ischemia. Functional outcomes and perfusion were measured using standardized scores, laser Doppler imaging, microCT, histology and immunofluorescence. Functional outcomes and blood flow were improved in hiPSC-SMC-treated mice compared with controls (Tarlov score, p < 0.05; Faber score, p < 0.05; flow, p = 0.054). hiPSC-SMC-treated mice showed fewer gastrocnemius fibers (p < 0.0001), increased fiber area (p < 0.0001), and enhanced capillary density (p < 0.01); microCT showed more arterioles (p < 0.05) and increased numbers of M2-type macrophages (p < 0.0001). Vascular endothelial growth factor (VEGF) expression in ischemic limbs was significantly elevated with hiPSC-SMC treatment (p < 0.05), and inhibition of VEGFR-2 with SU5416 was associated with fewer capillaries in hiPSC-SMC-treated limbs (p < 0.0001). hiPSC-SMC promote VEGF-mediated angiogenesis, leading to improved hindlimb ischemia. Stem cell therapy using iPSC-derived cells may represent a novel and potentially translatable therapy for limb-threatening ischemia.

Cytokines are potent immune modulating agents but are not ideal medicines in their natural form due to their short half-life and pleiotropic systemic effects. NKTR-214 is a clinical-stage biologic that comprises interleukin-2 (IL2) protein bound by multiple releasable polyethylene glycol (PEG) chains. In this highly PEG-bound form, the IL2 is inactive; therefore, NKTR-214 is a biologic prodrug. When administered in vivo, the PEG chains slowly release, creating a cascade of increasingly active IL2 protein conjugates bound by fewer PEG chains. The 1-PEG-IL2 and 2-PEG-IL2 species derived from NKTR-214 are the most active conjugated-IL2 species. Free-IL2 protein is undetectable in vivo as it is eliminated faster than formed. The PEG chains on NKTR-214 are located at the region of IL2 that contacts the alpha (α) subunit of the heterotrimeric IL2 receptor complex, IL2Rαβγ, reducing its ability to bind and activate the heterotrimer. The IL2Rαβγ complex is constitutively expressed on regulatory T cells (Tregs). Therefore, without the use of mutations, PEGylation reduces the affinity for IL2Rαβγ to a greater extent than for IL2Rβγ, the receptor complex predominant on CD8 T cells. NKTR-214 treatment in vivo favors activation of CD8 T cells over Tregs in the tumor microenvironment to provide anti-tumor efficacy in multiple syngeneic models. Mechanistic modeling based on in vitro and in vivo kinetic data provides insight into the mechanism of NKTR-214 pharmacology. The model reveals that conjugated-IL2 protein derived from NKTR-214 occupy IL-2Rβγ to a greater extent compared to free-IL2 protein. The model accurately describes the sustained in vivo signaling observed after a single dose of NKTR-214 and explains how the properties of NKTR-214 impart a unique kinetically-controlled immunological mechanism of action.

IntroductionMost studies investigating disability outcomes following injury have examined hospitalised patients. It is not known whether variables associated with disability outcomes are similar for injured people who are not hospitalised.AimsThis paper compares the prevalence of disability 24 months after injury for participants in the Prospective Outcomes of Injury Study who were hospitalised and those non-hospitalised, and also seeks to identify pre-injury and injury-related predictors of disability among hospitalised and non-hospitalised participants.MethodsParticipants, aged 18-64 years, were recruited from an injury claims register managed by New Zealand's no-fault injury compensation insurer after referral by health care professionals. A wide range of pre-injury socio-demographic, health and psychosocial characteristics were collected, as well as injury-related characteristics; outcome is assessed using the WHODAS. Multivariable models estimating relative risks of disability for hospitalised and non-hospitalised participants were developed using Poisson regression methods.ResultsOf 2856 participants, analyses were restricted to 2184 (76%) participants for whom both pre-injury and 24 month WHODAS data were available. Of these, 25% were hospitalised. In both hospitalised and non-hospitalised groups, 13% experience disability (WHODAS≥10) 24 months after injury; higher than pre-injury (5%). Of 28 predictor variables, seven independently placed injured participants in the hospitalised group at increased risk of disability 24 months after injury; eight in the non-hospitalised. Only four predictors (pre-injury disability, two or more pre-injury chronic conditions, pre-injury BMI≥30 and trouble accessing healthcare services) were common to both the hospitalised and non-hospitalised groups. There is some evidence to suggest that among the hospitalised group, Māori have higher risk of disability relative to non-Māori.ConclusionsAt 24 months considerable disability is borne, equally, by hospitalised and non-hospitalised groups. However, predictors of disability are not necessarily consistent between the hospitalised and non-hospitalised groups, suggesting caution in generalising results from one group to the other.

Bone morphogenetic proteins (BMPs) are highly conserved morphogens that are essential for normal development. BMP-2 is highly expressed in the majority of non-small cell lung carcinomas (NSCLC) but not in normal lung tissue or benign lung tumors. The effects of the BMP signaling cascade on the growth and survival of cancer cells is poorly understood. We show that BMP signaling is basally active in lung cancer cell lines, which can be effectively inhibited with selective antagonists of the BMP type I receptors. Lung cancer cell lines express alk2, alk3, and alk6 and inhibition of a single BMP receptor was not sufficient to decrease signaling. Inhibition of more than one type I receptor was required to decrease BMP signaling in lung cancer cell lines. BMP receptor antagonists and silencing of BMP type I receptors with siRNA induced cell death, inhibited cell growth, and caused a significant decrease in the expression of inhibitor of differentiation (Id1, Id2, and Id3) family members, which are known to regulate cell growth and survival in many types of cancers. BMP receptor antagonists also decreased clonogenic cell growth. Knockdown of Id3 significantly decreased cell growth and induced cell death of lung cancer cells. H1299 cells stably overexpressing Id3 were resistant to growth suppression and induction of cell death induced by the BMP antagonist DMH2. These studies suggest that BMP signaling promotes cell growth and survival of lung cancer cells, which is mediated through its regulation of Id family members. Selective antagonists of the BMP type I receptors represents a potential means to pharmacologically treat NSCLC and other carcinomas with an activated BMP signaling cascade.

IntroductionTo reduce the burden on injury survivors and their supporters, factors associated with poor outcomes need to be identified so that timely post-injury interventions can be implemented. To date, few studies have investigated outcomes for both those who were hospitalised and those who were not.AimTo describe the prevalence and to identify pre-injury and injury-related predictors of disability among hospitalised and non-hospitalised people, three months after injury.MethodsParticipants in the Prospective Outcomes of Injury Study were aged 18-64 years and on an injury entitlement claims register with New Zealand's no-fault injury compensation insurer, following referral by healthcare professionals. A wide range of pre-injury demographic, health and injury-related characteristics were collected at interview. Participants were categorised as 'hospitalised' if they were placed on New Zealand's National Minimum Data Set within seven days of the injury event. Injury severity scores (NISS) and 12 injury categories were derived from ICD-10 codes. WHODAS assessed disability. Multivariable analyses examined relationships between explanatory variables and disability.ResultsOf 2856 participants, 2752 (96%) had WHODAS scores available for multivariable analysis; 673 were hospitalised; 2079 were not. Disability was highly prevalent among hospitalised (53.6%) and non-hospitalised (39.4%) participants, three-months after injury. In both groups, pre-injury disability, obesity and higher injury severity were associated with increased odds of post-injury disability. A range of other factors were associated with disability in only one group: e.g. female, ≥ 2 chronic conditions and leg fracture among hospitalised; aged 35-54 years, trouble accessing healthcare, spine or lower extremity sprains/dislocations and assault among non-hospitalised.SignificanceDisability was highly prevalent among both groups yet, with a few exceptions, factors associated with disability were not common to both groups. Where possible, including a range of injured people in studies, hospitalised and not, will increase understanding of the burden of disability in the sub-acute phase.