A Brief Tool to Screen Patients for Precarious Employment: A Validation Study.

PURPOSE: Precarious employment, defined by temporary contracts, unstable employment, or job insecurity, is increasingly common and is associated with inconsistent access to benefits, lower income, and greater exposure to physical and psycholosocial hazards. Clinicians can benefit from a simple approach to screen for precarious employment to improve their understanding of a patient's social context, help with diagnoses, and inform treatment plans and intersectional interventions. Our objective was to validate a screening tool for precarious employment. METHODS: We used a 3-item screening tool that covered key aspects of precarious employment: non-standard employment, variable income, and violations of occupational health and safety rights and protections. Answers were compared with classification using the Poverty and Employment Precarity in Southern Ontario Employment Index. Participants were aged 18 years and older, fluent in English, and employed. They were recruited in 7 primary care clinic waiting rooms in Toronto, Canada over 12 months. RESULTS: A total of 204 people aged 18-72 years (mean 38 [SD 11.3]) participated, of which 93 (45.6%) identified as men and 119 (58.3%) self-reported as White. Participants who reported 2 or more of the 3 items as positive were almost 4 times more likely to be precariously employed (positive likelihood ratio = 3.84 [95% CI, 2.15-6.80]). CONCLUSIONS: A 3-item screening tool can help identify precarious employment. Our tool is useful for starting a conversation about employment precarity and work conditions in clinical settings. Implementation of this screening tool in health settings could enable better targeting of resources for managing care and connecting patients to legal and employment support services.

Continuous palliative sedation until death: a qualitative study of palliative care clinicians' experiences.

BACKGROUND: The practice of continuous palliative sedation until death is the subject of much medical and ethical debate, which is reflected in the inconsistency that persists in the literature regarding the definition and indications of palliative sedation. AIM: This study aims to gain a better understanding of palliative care clinicians' experiences with continuous palliative sedation. DESIGN: We conducted a qualitative study based on focus group discussions. SETTING/PARTICIPANTS: We conducted six focus groups with a total of 28 palliative care clinicians (i.e., 15 nurses, 12 physicians, and 1 end-of-life doula) from diverse care settings across Canada, where assisted dying has recently been legalized. RESULTS: An interpretative phenomenological analysis was used to consolidate the data into six key themes: responding to suffering; grappling with uncertainty; adapting care to ensure ongoing quality; grounding clinical practice in ethics; combining medical expertise, relational tact, and reflexivity; and offering an alternative to assisted death. CONCLUSIONS: Interaction with the patient's family, uncertainty about the patient's prognosis, the concurrent practice of assisted dying, and the treatment of existential suffering influence the quality of sedation and indicate a lack of clear palliative care guidelines. Nevertheless, clinicians exhibit a reflective and adaptive capacity that can facilitate good practice.

Hybrid Shear-thinning Hydrogel Integrating Hyaluronic Acid with ROS-Responsive Nanoparticles.

Nanoparticle (NP) supra-assembly offers unique opportunities to tune macroscopic hydrogels' mechanical strength, material degradation, and drug delivery properties. Here, synthetic, reactive oxygen species (ROS)-responsive NPs are physically crosslinked with hyaluronic acid (HA) through guest-host chemistry to create shear-thinning NP/HA hydrogels. A library of triblock copolymers composed of poly(propylene sulfide)-bl-poly(N,N-dimethylacrylamide)-bl-poly(N,N-dimethylacrylamide-co-N-(1-adamantyl)acrylamide) are synthesized with varied triblock architectures and adamantane grafting densities and then self-assembled into NPs displaying adamantane on their corona. Self-assembled NPs are mixed with ß-cyclodextrin grafted HA to yield eighteen NP/HA hydrogel formulations. The NP/HA hydrogel platform demonstrates superior mechanical strength to HA-only hydrogels, susceptibility to oxidative/enzymatic degradation, and inherent cell-protective, antioxidant function. The performance of NP/HA hydrogels is shown to be affected by triblock architecture, guest/host grafting densities, and HA composition. In particular, the length of the hydrophilic second block and adamantane grafting density of self-assembled NPs significantly impacts hydrogel mechanical properties and shear-thinning behavior, while ROS-reactivity of poly(propylene sulfide) protects cells from cytotoxic ROS and reduces oxidative degradation of HA compared to HA-only hydrogels. This work provides insight into polymer structure-function considerations for designing hybrid NP/HA hydrogels and identifies antioxidant, shear-thinning hydrogels as promising injectable delivery platforms for small molecule drugs and therapeutic cells.

Immunotherapy for GI Malignancies, Ready for Prime Time?

Gastrointestinal (GI) cancers include esophageal, gastric, pancreatic, hepatobiliary, and colorectal malignancies. Immunotherapy has proved to be an important treatment method for cancer, and its use for a wide range of GI malignancies has been evaluated recently. This article discusses the type and mechanism of various immunotherapies under investigation in GI cancer. The study also reviews recent clinical trials, with a particular focus on overall survival, and discusses their achievements and limitations. Immunotherapy has shown efficacy for microsatellite instability high colorectal cancer and some promise in some gastroesophageal junction and gastric cancers. Meanwhile, it has not been effective for pancreatic or neuroendocrine tumors. The identification of novel biomarkers likely will guide selection of therapy for individual patients. Nevertheless, immunotherapy for GI cancers is in its infancy, and many other classes of immune therapies are being developed besides anti-PD1 and anti-PDL1. Thus, although immunotherapy has not seen a dramatic advance to date, it still has great potential.

Pediatric Bradycardia Is Undertreated in the Prehospital Setting: A Retrospective Multi-Agency Analysis.

BACKGROUND: Bradycardia is the most common terminal cardiac electrical activity in children, and early recognition and treatment is necessary to avoid cardiac arrest. Interventions such as oxygen, chest compressions, epinephrine, and atropine recommended by American Heart Association (AHA) Pediatric Advanced Life support (PALS) guidelines have been shown to improve outcomes (including higher survival rates) for inpatient pediatric patients with bradycardia. However, little is known about the epidemiology of pediatric prehospital bradycardia. We sought to investigate the incidence and management of pediatric bradycardia in the prehospital setting by emergency medical services (EMS). METHODS: This was a retrospective study of 911 scene response prehospital encounters for patients ages 0-18 years in 2019 from the United States ESO Research Data Collaborative. We defined age-based bradycardia per the 2015 AHA PALS guidelines. We performed general descriptive statistics and a univariate analysis examining any PALS-recommended interventions in the presence of altered mental status, hypotension for age, and a first heart rate less than 60. RESULTS: Of 7,422,710 encounters in the 2019 ESO Data Collaborative, 1,209 patients met inclusion criteria. Most (58.5%) were male, and the median age was 2 years (interquartile range 0-13 years). One-quarter (24.7%) of patients received fluids, and bag-valve mask ventilation was the most common airway intervention (12.1% of patients). Receipt of any PALS-recommended interventions was associated with age-adjusted hypotension (odds ratio (OR) 4.0, 95% confidence interval (CI) 3.9-5.4) and altered mental status (OR 15.5, 95% CI 10.7-22.3), but not a first heart rate less than 60 bpm (OR 0.9, 95% CI 0.6-1.1). CONCLUSIONS: To our knowledge, this study is the first to examine the incidence and management of prehospital pediatric bradycardia. Incidence was rare, but adherence to PALS guidelines was variable. Further research and education are needed to ensure proper prehospital treatment of pediatric bradycardia.

Inducible expression of (pp)pGpp synthetases in Staphylococcus aureus is associated with activation of stress response genes.

The stringent response is characterized by the synthesis of the messenger molecules pppGpp, ppGpp or pGpp (here collectively designated (pp)pGpp). The phenotypic consequences resulting from (pp)pGpp accumulation vary among species and can be mediated by different underlying mechanisms. Most genome-wide analyses have been performed under stress conditions, which often mask the immediate effects of (pp)pGpp-mediated regulatory circuits. In Staphylococcus aureus, (pp)pGpp can be synthesized via the RelA-SpoT-homolog, RelSau upon amino acid limitation or via one of the two small (pp)pGpp synthetases RelP or RelQ upon cell wall stress. We used RNA-Seq to compare the global effects in response to induction of the synthetase of rel-Syn (coding for the enzymatic region of RelSau) or relQ without the need to apply additional stress conditions. Induction of rel-Syn resulted in changes in the nucleotide pool similar to induction of the stringent response via the tRNA synthetase inhibitor mupirocin: a reduction in the GTP pool, an increase in the ATP pool and synthesis of pppGpp, ppGpp and pGpp. Induction of all three enzymes resulted in similar changes in the transcriptome. However, RelQ was less active than Rel-Syn and RelP, indicating strong restriction of its (pp)pGpp-synthesis activity in vivo. (pp)pGpp induction resulted in the downregulation of many genes involved in protein and RNA/DNA metabolism. Many of the (pp)pGpp upregulated genes are part of the GTP sensitive CodY regulon and thus likely regulated through lowering of the GTP pool. New CodY independent transcriptional changes were detected including genes involved in the SOS response, iron storage (e.g. ftnA, dps), oxidative stress response (e.g., perR, katA, sodA) and the psmα1-4 and psmß1-2 operons coding for cytotoxic, phenol soluble modulins (PSMs). Analyses of the ftnA, dps and psm genes in different regulatory mutants revealed that their (pp)pGpp-dependent regulation can occur independent of the regulators PerR, Fur, SarA or CodY. Moreover, psm expression is uncoupled from expression of the quorum sensing system Agr, the main known psm activator. The expression of central genes of the oxidative stress response protects the bacteria from anticipated ROS stress derived from PSMs or exogenous sources. Thus, we identified a new link between the stringent response and oxidative stress in S. aureus that is likely crucial for survival upon phagocytosis.

Collecting occupation and hazards information in primary care using O*NET.

OBJECTIVE: The objective of this study was to determine the feasibility of collecting occupation and occupational hazard data in a primary care setting, using the Occupational Information Network (O*NET) database to assist with classification. METHODS: We collected data from 204 employed adult primary care patients in Toronto, Canada, on their occupation and exposure to occupational hazards, and mapped their job titles to the O*NET database. We compared their self-reported occupational hazard exposures with the likelihood of exposure on O*NET. RESULTS: Exposure to repetitive arm movement was reported by 78%, to vapors/gas/dust/fumes by 30%, to noise by 30%, and to heavy loads by 31%. Significant differences in exposure to vapors/gas/dust/fumes were associated with work precarity. We matched the majority of job titles (89%) to O*NET categories. CONCLUSIONS: Collecting employment information in primary care setting was feasible, with the majority of job titles mapping onto O*NET classifications.

Gastric Neuroendocrine Tumors: Reappraisal of Type in Predicting Outcome.

BACKGROUND: Type I gastric neuroendocrine tumors (GNETs) are typically managed either expectantly or endoscopically. In contrast, locoregional surgery has been recommended for patients with type III GNETs because of the risk of metastasis. This study aimed to identify predictors of outcome independent of type in a contemporary cohort of GNET patients. METHODS: A single-institution retrospective cohort study of 121 patients with a pathologic diagnosis of primary GNET between January 2009 and June 2019 was performed. GNETs were designated as type 1 (n = 74) if atrophic gastritis was present, or as type III (n = 47) in the absence of atrophic gastritis. Demographic, clinical, and histopathologic factors were examined using Kaplan-Meier and multivariable Cox regression to assess the impact of various factors on recurrence and overall survival. RESULTS: Median follow-up for the entire cohort was 62.7 months. While there was no difference in OS in patients with different GNET types (p = 0.10), higher tumor grade (p = 0.02) and presence of nodal or distant metastases (p = 0.02) predicted worse survival on multivariable analysis. Among type III GNET patients, those with small (< 0.5 cm), grade 1 lesions ("low-risk") were less likely to develop metastases (0% versus 33%, p < 0.01) and more likely to survive (100% versus 67%, p < 0.01) at 5 years. CONCLUSIONS: Size and tumor grade predict recurrence and survival in patients with GNETs irrespective of type. Small, low-grade type III GNETs are associated with minimal risk of progression and may be managed accordingly.

Relationship between age and likelihood of lymph node metastases in patients with intermediate thickness melanoma (1.01-4.00 mm): A National Cancer Database study.

BACKGROUND: There is large variability in the risk of sentinel lymph node (SLN) positivity among patients with intermediate thickness melanoma (ITM), with a subgroup of patients exhibiting a low risk of nodal disease. OBJECTIVE: To identify a group of patients with ITM for whom the risk of nodal disease is low. METHODS: A retrospective cohort of patients with ITM who underwent wide excision and nodal evaluation from 2010 to 2013 was identified by using the National Cancer Database and analyzed for the presence of nodal disease. Classification and regression tree analysis identified the most important factors used in a model to identify groups at low risk of SLN positivity. RESULTS: Of 23,440 patients, 14.7% were found to have nodal metastasis. On classification and regression tree analysis, patients older than 55 years without lymphovascular invasion and with a lesion thickness less than 1.7 mm had an SLN positivity rate of 4.9%. A model using age and thickness in nonulcerated patients identified a low-risk subgroup with a corresponding SLN positivity rate of 4.7%. LIMITATIONS: This was a retrospective study, and the model developed requires prospective validation. CONCLUSIONS: Patient age is an important factor in estimating risk of SLN in patients with ITM and may help identify patients without ulceration who may be safely spared an SLN biopsy.

Prediction of Autograft Hamstring Size for Anterior Cruciate Ligament Reconstruction Using MRI.

BACKGROUND: Hamstring autografts with a diameter of less than 8 mm for ACL reconstruction have an increased risk of failure, but there is no consensus regarding the best method to predict autograft size in ACL reconstruction. QUESTIONS/PURPOSES: (1) What is the relationship between hamstring cross-section on preoperative MRI and intraoperative autograft size? (2) What is the minimum hamstring tendon cross-sectional area on MRI needed to produce an autograft of at least 8 mm at its thickest point? METHODS: This was a retrospective cohort study of 68 patients. We collectively reviewed patients who underwent ACL reconstruction by three separate fellowship-trained surgeons at the Carilion Clinic between April 2010 and July 2013. We searched the patient records database of each surgeon using the keyword "ACL". A total of 293 ACL reconstructions were performed during that time period. Of those, 23% (68 patients) had their preoperative MRI (1.5 T or 3 T magnet) performed at the Carilion Clinic with MRI confirmation of acute total ACL rupture. Exclusion criteria included previous ACL reconstructions, multiligamentous injuries, and history of acute hamstring injuries.After applying the exclusion criteria, there were 29 patients in the 1.5 T magnet group and 39 in the 3 T group. Median age (range) was 29 years (12 to 50) for the 1.5 T group and 19 years (9 to 43) for the 3 T group. The patients were 41% female in the 1.5 T group and 23% female in the 3 T group. Use of 1.5 T or 3 T magnets was based on clinical availability and scheduling. The graft's preoperative cross-sectional area was compared with the intraoperative graft's diameter. The MRI measurements were performed by a single musculoskeletal radiologist at the widest point of the medial femoral condyle and at the joint line. Intraoperative measurements were performed by recording the smallest hole the graft could fit through at its widest point. Pearson's correlation coefficients were calculated to determine the relationship between graft size and tendon cross-sectional area. A simple logistic regression analysis was used to calculate the cutoff cross-sectional areas needed for a graft measuring at least 8 mm at its thickest point. Intrarater reliability was evaluated based on re-measurement of 19 tendons, which produced an overall intraclass correlation coefficient (ICC) of 0.96 95% (CI 0.93 to 0.98). A p value < 0.05 was considered significant. RESULTS: In general, the correlation between MRI-measured hamstring thickness and hamstring graft thickness as measured in the operating room were good but not excellent. The three measurements that demonstrated the strongest correlation with graft size in the 1.5 T group were the semitendinosus at the medial femoral condyle (r = 0.69; p < 0.001), the semitendinosus and gracilis at the medial femoral condyle (r = 0.70; p < 0.001), and the mean semitendinosus and gracilis (r = 0.64; p < 0.001). These three measurements had correlation values of 0.53, 0.56, and 0.56, respectively, in the 3 T MRI group (all p values < 0.001). To create an 8-mm hamstring autograft, the mean semitendinosus plus gracilis cutoff values areas were 18.8 mm and 17.5 mm for the 1.5 T and 3.0 T MRI groups, respectively. CONCLUSIONS: Imaging performed according to routine knee injury protocol can be used to preoperatively predict the size of hamstring autografts for ACL reconstructions. In clinical practice, this can assist orthopaedic surgeons in graft selection and surgical planning. LEVEL OF EVIDENCE: Level II, diagnostic study.

Prognostic models for patients with brain metastases after stereotactic radiosurgery with or without whole brain radiotherapy: a validation study.

PURPOSE/OBJECTIVE(S): To compare the performance of five prognostic models [RTOG recursive partitioning analysis (RPA), Score Index for Radiosurgery in Brain Metastases (SIR), Barnholtz-Sloan-Kattan nomogram (BSKN), diagnosis-specific Graded Prognostic Assessment (dsGPA), and Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA)] against actual survival in patients with brain metastases treated with SRS +/- WBRT. MATERIALS/METHODS: 100 consecutive patients treated with SRS +/- WBRT between January 2006 and July 2012 were retrospectively analyzed. Patients were binned according to 33 percentiles of the predicted survival distribution for the BSKN and dsGPA models to compare with LungmolGPA, RPA and SIR. Pearson's correlation coefficients between predicted and observed survival were estimated to quantify the proportion of variance in observed survival. RESULTS: Median survival for the entire cohort was 13.5 months, with predicted vs actual MS by BSKN, SIR, dsGPA, RPA, adenocarcinoma Lung-molGPA, and nonadenocarcinoma Lung-molGPA was 3.8 vs 15.6 months, 7 vs 13.5 months, 9.4 vs 13.5 months, 10.3 vs 13.5 months, 13.7 vs 13.7 months, and 9.8 vs 9.7 months, respectively. The BSKN model and adenocarcinoma LungmolGPA created three groups with a statistically significantly different MS (p = 0.002 and p = 0.01, respectively). CONCLUSION: All models under-predicted MS and only the BSKN and Lung-molGPA model stratified patients into three risk groups with statistically significant actual MS. The prognostic groupings of the adenocarcinoma Lung-molGPA group was the best predictor of MS, and showed that we are making improvements in our prognostic ability by utilizing molecular information that is much more widely available in the current treatment era.

What predicts early volumetric edema increase following stereotactic radiosurgery for brain metastases?

A volumetric analysis of pre- and post-radiosurgery (PreSRS and PostSRS) edema in patients with cerebral metastases was performed to determine factors of a predictive model assessing the risk of developing increased edema relatively early after SRS. One-hundred-fourteen metastases in 55 patients were analyzed. Selection for this analysis required an MRI ≤ 30 days before SRS and an MRI ≤ 100 days after SRS. Tumor volumes were calculated on PreSRS, SRS, and PostSRS T1-weighted postgadolinium images while edema volumes were calculating using PreSRS and PostSRS fluid-attenuated inversion recovery MR images. An increase in edema was defined as an increase in measurable edema of at least 5%. We developed and evaluated a model predicting the relative risk (RR) of increased edema after SRS. Peritumoral edema increased in 18% (21/114) of the analyzed lesions. Melanoma/renal histology, recursive partitioning analysis class III, and prior WBRT carried RRs of developing postSRS edema increase of 2.45, 2.48, and 3.16, respectively (all P values <0.05). The PreSRS edema/tumor ratio predicted for a RR of 1.007/ratio unit, and steroid dose at time of SRS predicted for a RR of 0.89/mg (all P values <0.05). A predictive model for assessing the RR of increased edema after SRS was developed based from these data and may be useful in identifying patients who might benefit from prophylactic anti-edema therapies before, during, or after SRS. This model could be used as the basis of inclusion criteria for prospective trials investigating novel anti-edema therapies.

Tooth-Size Discrepancies in Patients Requiring Mandibular Advancement Surgery.

PURPOSE: Numerous studies have shown that tooth size is an important key to ideal occlusion. Bolton (Angle Orthod 28:13, 1958; 48:504, 1962) described a constant ratio between the widths of the upper and lower teeth that must be present to achieve an optimal occlusion. The purpose of this study was to determine the incidence of Bolton discrepancies in patients with Class II malocclusion scheduled for mandibular advancement surgery. PATIENTS AND METHODS: This study included 126 patients (40 male, 86 female) with Class II malocclusion who had at least a mandibular advancement as part of their surgical treatment. The mesiodistal widths of the 6 anterior maxillary and mandibular teeth were measured on preoperative models using a caliper. The measurements were used to compute the anterior Bolton ratio. RESULTS: Seventy-three of 126 patients (57.9%) were found to have an anterior Bolton ratio greater than the Bolton norm, indicating too much lower tooth mass compared with the upper mass or too little upper tooth mass compared with the lower mass. CONCLUSION: Tooth-size discrepancies are common in patients requiring mandibular advancement surgery. This can make it difficult to advance the mandible into a solid Class I relation at the time of surgery. Bolton discrepancies should be considered when planning treatment with presurgical orthodontics. In addition, if necessary, the width of the lower incisors should be decreased or a space distal to the maxillary lateral incisors should be created to allow the establishment of a solid Class I canine occlusion at the time of surgery.

Tyrosine Kinase Inhibition Activates Intratumoral γδ T Cells in Gastrointestinal Stromal Tumor.

γδ T cells are a rare but potent subset of T cells with pleiotropic functions. They commonly reside within tumors but the response of γδ T cells to tyrosine kinase inhibition is unknown. To address this, we studied a genetically engineered mouse model of gastrointestinal stromal tumor (GIST) driven by oncogenic Kit signaling that responds to the Kit inhibitor imatinib. At baseline, γδ T cells were antitumoral, as blockade of either γδ T-cell receptor or IL17A increased tumor weight and decreased antitumor immunity. However, imatinib therapy further stimulated intratumoral γδ T cells, as determined by flow cytometry and single-cell RNA sequencing (scRNA-seq). Imatinib expanded a highly activated γδ T-cell subset with increased IL17A production and higher expression of immune checkpoints and cytolytic effector molecules. Consistent with the mouse model, γδ T cells produced IL17A in fresh human GIST specimens, and imatinib treatment increased γδ T-cell gene signatures, as measured by bulk tumor RNA-seq. Furthermore, tumor γδ T cells correlated with survival in patients with GIST. Our findings highlight the interplay between tumor cell oncogene signaling and antitumor immune responses and identify γδ T cells as targets for immunotherapy in GIST.

Emerging probing perspective of two-dimensional materials physics: terahertz emission spectroscopy.

Terahertz (THz) emission spectroscopy (TES) has emerged as a highly effective and versatile technique for investigating the photoelectric properties of diverse materials and nonlinear physical processes in the past few decades. Concurrently, research on two-dimensional (2D) materials has experienced substantial growth due to their atomically thin structures, exceptional mechanical and optoelectronic properties, and the potential for applications in flexible electronics, sensing, and nanoelectronics. Specifically, these materials offer advantages such as tunable bandgap, high carrier mobility, wideband optical absorption, and relatively short carrier lifetime. By applying TES to investigate the 2D materials, their interfaces and heterostructures, rich information about the interplay among photons, charges, phonons and spins can be unfolded, which provides fundamental understanding for future applications. Thus it is timely to review the nonlinear processes underlying THz emission in 2D materials including optical rectification, photon-drag, high-order harmonic generation and spin-to-charge conversion, showcasing the rich diversity of the TES employed to unravel the complex nature of these materials. Typical applications based on THz emissions, such as THz lasers, ultrafast imaging and biosensors, are also discussed. Step further, we analyzed the unique advantages of spintronic terahertz emitters and the future technological advancements in the development of new THz generation mechanisms leading to advanced THz sources characterized by wide bandwidth, high power and integration, suitable for industrial and commercial applications. The continuous advancement and integration of TES with the study of 2D materials and heterostructures promise to revolutionize research in different areas, including basic materials physics, novel optoelectronic devices, and chips for post-Moore's era.