Leveraging big data of immune checkpoint blockade response identifies novel potential targets.

BACKGROUND: The development of immune checkpoint blockade (ICB) has changed the way we treat various cancers. While ICB produces durable survival benefits in a number of malignancies, a large proportion of treated patients do not derive clinical benefit. Recent clinical profiling studies have shed light on molecular features and mechanisms that modulate response to ICB. Nevertheless, none of these identified molecular features were investigated in large enough cohorts to be of clinical value. MATERIALS AND METHODS: Literature review was carried out to identify relevant studies including clinical dataset of patients treated with ICB [anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) or the combination] and available sequencing data. Tumor mutational burden (TMB) and 37 previously reported gene expression (GE) signatures were computed with respect to the original publication. Biomarker association with ICB response (IR) and survival (progression-free survival/overall survival) was investigated separately within each study and combined together for meta-analysis. RESULTS: We carried out a comparative meta-analysis of genomic and transcriptomic biomarkers of IRs in over 3600 patients across 12 tumor types and implemented an open-source web application (predictIO.ca) for exploration. TMB and 21/37 gene signatures were predictive of IRs across tumor types. We next developed a de novo GE signature (PredictIO) from our pan-cancer analysis and demonstrated its superior predictive value over other biomarkers. To identify novel targets, we computed the T-cell dysfunction score for each gene within PredictIO and their ability to predict dual PD-1/CTLA-4 blockade in mice. Two genes, F2RL1 (encoding protease-activated receptor-2) and RBFOX2 (encoding RNA-binding motif protein 9), were concurrently associated with worse ICB clinical outcomes, T-cell dysfunction in ICB-naive patients and resistance to dual PD-1/CTLA-4 blockade in preclinical models. CONCLUSION: Our study highlights the potential of large-scale meta-analyses in identifying novel biomarkers and potential therapeutic targets for cancer immunotherapy.

How long does it take patients to find a new primary care physician when theirs retires: a population-based, longitudinal study.

BACKGROUND: The retirement of a family physician can represent a challenge in accessibility and continuity of care for patients. In this population-based, longitudinal cohort study, we assess whether and how long it takes for patients to find a new majority source of primary care (MSOC) when theirs retires, and we investigate the effect of demographic and clinical characteristics on this process. METHODS: We used provincial health insurance records to identify the complete cohort of patients whose majority source of care left clinical practice in either 2007/2008 or 2008/2009 and then calculated the number of days between their last visit with their original MSOC and their first visit with their new one. We compared the clinical and sociodemographic characteristics of patients who did and did not find a new MSOC in the three years following their original physician's retirement using Chi-square and Fisher's exact test. We also used Cox proportional hazards models to determine the adjusted association between patient age, sex, socioeconomic status, location and morbidity level (measured using Johns Hopkins' Aggregated Diagnostic Groupings), and time to finding a new primary care physician. We produce survival curves stratified by patient age, sex, income and morbidity. RESULTS: Fifty-four percent of patients found a new MSOC within the first 12 months following their physician's retirement. Six percent of patients still had not found a new physician after 36 months. Patients who were older and had higher levels of morbidity were more likely to find a new MSOC and found one faster than younger, healthier patients. Patients located in more urban regional health authorities also took longer to find a new MSOC compared to those in rural areas. CONCLUSIONS: Primary care physician retirements represent a potential threat to accessibility; patients followed in this study took more than a year on average to find a new MSOC after their physician retired. Providing programmatic support to retiring physicians and their patients, as well as addressing shortages of longitudinal primary care more broadly could help to ensure smoother retirement transitions.

Advances in the Direct Study of Carbon Burning in Massive Stars.

The ^{12}C+^{12}C fusion reaction plays a critical role in the evolution of massive stars and also strongly impacts various explosive astrophysical scenarios. The presence of resonances in this reaction at energies around and below the Coulomb barrier makes it impossible to carry out a simple extrapolation down to the Gamow window-the energy regime relevant to carbon burning in massive stars. The ^{12}C+^{12}C system forms a unique laboratory for challenging the contemporary picture of deep sub-barrier fusion (possible sub-barrier hindrance) and its interplay with nuclear structure (sub-barrier resonances). Here, we show that direct measurements of the ^{12}C+^{12}C fusion cross section may be made into the Gamow window using an advanced particle-gamma coincidence technique. The sensitivity of this technique effectively removes ambiguities in existing measurements made with gamma ray or charged-particle detection alone. The present cross-section data span over 8 orders of magnitude and support the fusion-hindrance model at deep sub-barrier energies.

Pharmacokinetics and pharmacodynamics of the novel monobactam LYS228 in a neutropenic murine thigh model of infection.

Objectives: The neutropenic murine thigh infection model and a dose-fractionation approach were used to determine the pharmacokinetic/pharmacodynamic (PK/PD) relationship of LYS228, a novel monobactam antibiotic with activity against Enterobacteriaceae including carbapenem-resistant strains. Methods: Mice (n = 4 per group) were inoculated with Enterobacteriaceae strains via intramuscular injection. Two hours post-bacterial inoculation, treatment with LYS228 was initiated. Animals were euthanized with CO2 24 h after the start of therapy and bacterial counts (log10 cfu) per thigh were determined. PK parameters were calculated using free (f) plasma drug levels. Results: Following a dose-fractionation study, non-linear regression analysis determined that the predominant PK/PD parameter associated with antibacterial efficacy of LYS228 was the percentage of the dosing interval that free drug concentrations remained above the MIC (%fT>MIC). In a dose-dependent manner, LYS228 reduced the thigh bacterial burden in models established with Enterobacteriaceae producing ß-lactamase enzymes of all classes (e.g. ESBLs, NDM-1, KPC, CMY-2 and OXA-48). The range of the calculated static dose was 86-649 mg/kg/day for the isolates tested, and the magnitude of the driver of efficacy was 37-83 %fT>MIC. %fT>MIC was confirmed as the parameter predominantly driving efficacy as evidenced by a strong coefficient of determination (r2 = 0.68). Neutrophils had minimal impact on the effect of LYS228 in the murine thigh infection model. Conclusions: LYS228 is efficacious in murine thigh infection models using ß-lactamase-producing strains of Enterobacteriaceae, including those expressing metallo-ß-lactamases, ESBLs and serine carbapenemases, with the PK/PD driver of efficacy identified as %T>MIC.

Trends in Providing Out-of-Office, Urgent After-Hours, and On-Call Care in British Columbia.

PURPOSE: Providing care in alternative (non-office) locations and outside office hours are important elements of access and comprehensiveness of primary care. We examined the trends in and determinants of the services provided in a cohort of primary care physicians in British Columbia, Canada. METHODS: We used physician-level payments for all primary care physicians practicing in British Columbia from 2006-2007 through 2011-2012. We examined the association between physician demographics and practice characteristics and payment for care in alternative locations and after hours across rural, urban, and metropolitan areas using longitudinal mixed-effects models. RESULTS: The proportion of physicians who provided care in alternative locations and after hours declined significantly during the period, in rural, urban, and metropolitan practices. Declines ranged from 5% for long-term care facility visits to 22% for after-hours care. Female physicians, and those in the oldest age category, had lower odds of providing care at alternative locations and for urgent after-hours care. Compared with those practicing in metropolitan centers, physicians working in rural areas had significantly higher odds of providing care both in alternative locations and after hours. CONCLUSION: Care provided in non-office locations and after office hours declined significantly during the study period. Jurisdictions where providing these services are not mandated, and where similar workforce demographic shifts are occurring, may experience similar accessibility challenges.

A unique schedule of palonosetron, ondansetron, and dexamethasone for the prevention of delayed nausea and vomiting in patients receiving myeloablative chemotherapy.

Myeloablative chemotherapy administered prior to autologous stem cell transplantation (auto-SCT) is associated with a significant amount of chemotherapy-induced nausea and vomiting (CINV). We conducted a phase II trial to assess the safety, efficacy, and impact on quality of life when palonosetron (PAL) 0.25 mg combined with dexamethasone were given on the final or only day of myeloablative chemotherapy for auto-SCT. The primary end point of this study was the incidence of achieving a delayed CINV complete response defined as no emetic episode and no use of rescue medications during the 24-120 h period post chemotherapy. Eighty-five patients were enrolled in the study and received PAL. A delayed CINV complete response was achieved in 15% of patients. A multivariate analysis demonstrated no associated differences between age, gender, diagnosis, or regimen. By day 5 after PAL, the mean nausea severity was 0.91 ± 2.45 vs. 0.09 ± 1.58 at baseline (p = 0.012). Quality of life measurements demonstrated similar quality of life between baseline and day 3. By day 6 however, nausea alone had a statistically significant impact on quality of life. In our study, PAL controlled nausea severity and sustained quality of life, but further strategies are needed to control delayed CINV associated with the auto-SCT process.

Embolus Analog Trajectory Paths Under Physiological Flowrates Through Patient-Specific Aortic Arch Models.

Atrial fibrillation (AF) is the most common irregular heartbeat among the world's population and is a major contributor to cardiogenic embolisms and acute ischemic stroke (AIS). However, the role AF flow plays in the trajectory paths of cardiogenic emboli has not been experimentally investigated. A physiological simulation system was designed to analyze the trajectory patterns of bovine embolus analogs (EAs) (n = 720) through four patient-specific models, under three flow conditions: steady flow, normal pulsatile flow, and AF pulsatile flow. It was seen that EA trajectory paths were proportional to the percentage flowrate split of 25-31% along the branching vessels. Overall, AF flow conditions increased trajectories through the left- (LCCA) and right (RCCA)-common carotid artery by 25% with respect to normal pulsatile flow. There was no statistical difference in the distribution of clot trajectories when the clot was released from the right, left, or anterior positions. Significantly, more EAs traveled through the brachiocephalic trunk (BCT) than through the LCCA or the left subclavian. Yet of the EAs that traveled through the common carotid arteries, there was a greater affiliation toward the LCCA compared to the RCCA (p < 0.05).

Is attending birth dying out? Trends in obstetric care provision among primary care physicians in British Columbia.

OBJECTIVE: To examine trends in and sociodemographic predictors of the provision of obstetric care within the primary care context among physicians in British Columbia (BC). DESIGN: Population-based, longitudinal cohort study using administrative data. SETTING: British Columbia. PARTICIPANTS: All primary care physicians practising in BC between 2005-2006 and 2011-2012. MAIN OUTCOME MEASURES: Fee-for-service payment records were used to identify the provision of prenatal and postnatal care and deliveries. The proportions of physicians who attended deliveries and who included any obstetric care provision in their practices were examined over time using longitudinal mixed-effects log-linear models. RESULTS: The proportion of physicians attending deliveries or providing any obstetric care declined significantly over the study period (deliveries: odds ratio [OR] of 0.92, 95% CI 0.89-0.95; obstetric care: OR = 0.92, 95% CI 0.89-0.95), and obstetric care provision accounted for a smaller proportion of overall practice activity (OR = 0.96, 95% CI 0.94-0.99). Female physicians had higher odds of including obstetric care in their practices (OR = 1.46, 95% CI 1.27-1.69), and by 2011-2012 had significantly higher odds of attending deliveries (OR = 1.22, 95% CI 1.05-1.38). Older physicians and those located in metropolitan centres were less likely to provide obstetric care or attend deliveries. CONCLUSION: The provision of obstetric care by primary care physicians in BC declined over this period, suggesting the possibility of a growing access issue, particularly in rural and remote communities where family physicians are often the sole providers of obstetric services.

Communication training interventions for family and professional carers of people living with dementia: a systematic review of effectiveness, acceptability and conceptual basis.

OBJECTIVES: To update previous reviews and provide a more detailed overview of the effectiveness, acceptability and conceptual basis of communication training-interventions for carers of people living with dementia. METHOD: We searched CINAHL Plus, MEDLINE and PsycINFO using a specific search and extraction protocol, and PRISMA guidelines. Two authors conducted searches and extracted studies that reported effectiveness, efficacy or acceptability data regarding a communication training-intervention for carers of people living with dementia. Risk of bias was assessed using the Cochrane Collaboration guidelines. Quality of qualitative studies was also systematically assessed. RESULTS: Searches identified 450 studies (after de-duplication). Thirty-eight studies were identified for inclusion in the review. Twenty-two studies focused on professional carers; 16 studies focused mainly on family carers. Training-interventions were found to improve communication and knowledge. Overall training-interventions were not found to significantly improve behaviour that challenges and caregiver burden. Acceptability levels were high overall, but satisfaction ratings were found to be higher for family carers than professional carers. Although many interventions were not supported by a clear conceptual framework, person-centred care was the most common framework described. CONCLUSION: This review indicated that training-interventions were effective in improving carer knowledge and communication skills. Effective interventions involved active participation by carers and were generally skills based (including practicing skills and discussion). However, improvements to quality of life and psychological wellbeing of carers and people living with dementia may require more targeted interventions.

Disrupted resting-state brain network properties in obesity: decreased global and putaminal cortico-striatal network efficiency.

BACKGROUND: The efficient organization and communication of brain networks underlie cognitive processing and their disruption can lead to pathological behaviours. Few studies have focused on whole-brain networks in obesity and binge eating disorder (BED). Here we used multi-echo resting-state functional magnetic resonance imaging (rsfMRI) along with a data-driven graph theory approach to assess brain network characteristics in obesity and BED. METHOD: Multi-echo rsfMRI scans were collected from 40 obese subjects (including 20 BED patients) and 40 healthy controls and denoised using multi-echo independent component analysis (ME-ICA). We constructed a whole-brain functional connectivity matrix with normalized correlation coefficients between regional mean blood oxygenation level-dependent (BOLD) signals from 90 brain regions in the Automated Anatomical Labeling atlas. We computed global and regional network properties in the binarized connectivity matrices with an edge density of 5%-25%. We also verified our findings using a separate parcellation, the Harvard-Oxford atlas parcellated into 470 regions. RESULTS: Obese subjects exhibited significantly reduced global and local network efficiency as well as decreased modularity compared with healthy controls, showing disruption in small-world and modular network structures. In regional metrics, the putamen, pallidum and thalamus exhibited significantly decreased nodal degree and efficiency in obese subjects. Obese subjects also showed decreased connectivity of cortico-striatal/cortico-thalamic networks associated with putaminal and cortical motor regions. These findings were significant with ME-ICA with limited group differences observed with conventional denoising or single-echo analysis. CONCLUSIONS: Using this data-driven analysis of multi-echo rsfMRI data, we found disruption in global network properties and motor cortico-striatal networks in obesity consistent with habit formation theories. Our findings highlight the role of network properties in pathological food misuse as possible biomarkers and therapeutic targets.

Impaired awareness of motor intention in functional neurological disorder: implications for voluntary and functional movement.

BACKGROUND: Functional neurological disorders (FNDs), also known as conversion disorder, are unexplained neurological symptoms unrelated to a neurological cause. The disorder is common, yet poorly understood. The symptoms are experienced as involuntary but have similarities to voluntary processes. Here we studied intention awareness in FND. METHOD: A total of 26 FND patients and 25 healthy volunteers participated in this functional magnetic resonance study using Libet's clock. RESULTS: FND is characterized by delayed awareness of the intention to move relative to the movement itself. The reporting of intention was more precise, suggesting that these findings are reliable and unrelated to non-specific attentional deficits. That these findings were more prominent with aberrant positive functional movement symptoms rather than negative symptoms may be relevant to impairments in timing for an inhibitory veto process. Attention towards intention relative to movement was associated with lower right inferior parietal cortex activity in FND, a region early in the processing of intention. During rest, aberrant functional connectivity was observed with the right inferior parietal cortex and other motor intention regions. CONCLUSIONS: The results converge with observations of low inferior parietal activity comparing involuntary with voluntary movement in FND, emphasizing core deficiencies in intention. Heightened precision of this impaired intention is consistent with Bayesian theories of impaired top-down priors that might influence the sense of involuntariness. A primary impairment in voluntary motor intention at an early processing stage might explain clinical observations of slowed effortful voluntary movement, heightened self-directed attention and underlie functional movements. These findings further suggest novel therapeutic targets.

Patterns of physician retirement and pre-retirement activity: a population-based cohort study.

BACKGROUND: Knowing when physicians retire and how they practise in the pre-retirement years is important information for health human resource planning. We identified patterns of retirement for physicians in British Columbia and the determinants of when and how physicians retire. METHODS: For this population-based retrospective cohort study, we used administrative data to examine activity levels and to identify retirements among BC's practising physicians. We included all physicians who were at least 50 years of age as of March 2006 and who had received payments for clinical services in at least 1 year between 2005/06 and 2011/12. We defined retirement as a permanent drop in monthly payments to less than $1667/month ($20 000/yr). We examined the patterns and timing of retirement by age, sex, specialty and location using linear and logistic regression models. RESULTS: Of the 4572 physicians who met the inclusion criteria, 1717 (37.6%) retired during the study period. The average age at retirement was 65.1 (standard deviation 7.8) years. Controlling for other demographic and practice characteristics, we found that women and physicians working in rural areas retired earlier, by 4.1 (95% confidence interval [CI] -4.9 to -3.2) years and 2.3 (95% CI -3.4 to -1.1) years, respectively. We found no difference in retirement age by specialty. We identified 4 patterns of pre-retirement activity: slow decline, rapid decline, maintenance and increasing activity. About 40% of physicians (440/1107) reduced their activity levels by at least 10% in the 3 years preceding retirement. INTERPRETATION: During the study period, physicians in BC - particularly women and those in rural areas - retired earlier than indicated by licensure and survey data. Many physicians reduced their practice activity in the pre-retirement years. These trends indicate that forecasts relying on licensure "head counts" are likely overestimating current and future physician supply.

A phase II study of axitinib (AG-013736) in patients with incurable adenoid cystic carcinoma.

BACKGROUND: Recurrent/metastatic adenoid cystic carcinoma (ACC) is an incurable disease with no standard treatments. The majority of ACCs express the oncogenic transcription factor MYB (also c-myb), often in the context of a MYB gene rearrangement. This phase II trial of the tyrosine kinase inhibitor (TKI) axitinib (Pfizer) tested the hypothesis that targeting pathways activated by MYB can be therapeutically effective for ACC. PATIENTS AND METHODS: This is a minimax two-stage, phase II trial that enrolled patients with incurable ACC of any primary site. Progressive or symptomatic disease was required. Patients were treated with axitinib 5 mg oral twice daily; dose escalation was allowed. The primary end point was best overall response (BOR). An exploratory analysis correlating biomarkers to drug benefit was conducted, including next-generation sequencing (NGS) in 11 patients. RESULTS: Thirty-three patients were registered and evaluable for response. Fifteen patients had the axitinib dose increased. Tumor shrinkage was achieved in 22 (66.7%); 3 (9.1%) had confirmed partial responses. Twenty-five (75.8%) patients had stable disease, 10 of whom had disease stability for >6 months. The median progression-free survival (PFS) was 5.7 months (range 0.92-21.8 months). Grade 3 axitinib-related toxicities included hypertension, oral pain and fatigue. A trend toward superior PFS was noted with the MYB/NFIB rearrangement, although this was not statistically significant. NGS revealed three tumors with 4q12 amplification, producing increased copies of axitinib-targeted genes PDGFR/KDR/KIT. Two 4q12 amplified patients achieved stable disease for >6 months, including one with significant tumor reduction and the longest PFS on study (21.8 months). CONCLUSIONS: Although the primary end point was not met, axitinib exhibited clinical activity with tumor shrinkage achieved in the majority of patients with progressive disease before trial enrollment. Analysis of MYB biomarkers and genomic profiling suggests the hypothesis that 4q12 amplified ACCs are a disease subset that benefit from TKI therapy.

Outcomes for patients with papillary thyroid cancer who do not undergo prophylactic central neck dissection.

BACKGROUND: The role of prophylactic central neck dissection (CND) in the management of papillary thyroid cancer (PTC) is controversial. This report describes outcomes of an observational approach in patients without clinical evidence of nodal disease in PTC. METHODS: All patients who had surgery between 1986 and 2010 without CND for PTC were identified. All patients had careful clinical assessment of the central neck during preoperative and perioperative evaluation, with any suspicious nodal tissue excised for analysis. The cohort included patients in whom lymph nodes had been removed, but no patient had undergone a formal neck dissection. Recurrence-free survival (RFS), central neck RFS and disease-specific survival (DSS) were calculated using the Kaplan-Meier method. RESULTS: Of 1798 patients, 397 (22.1 per cent) were men, 1088 (60.5 per cent) were aged 45 years or more, and 539 (30.0 per cent) had pT3 or pT4 disease. Some 742 patients (41.3 per cent) received adjuvant treatment with radioactive iodine. At a median follow-up of 46 months the 5-year DSS rate was 100 per cent. Five-year RFS and central neck RFS rates were 96.6 and 99.1 per cent respectively. CONCLUSION: Observation of the central neck is safe and should be recommended for all patients with PTC considered before and during surgery to be free of central neck metastasis.

An Experimental Evaluation of Device/Arterial Wall Compliance Mismatch for Four Stent-Graft Devices and a Multi-layer Flow Modulator Device for the Treatment of Abdominal Aortic Aneurysms.

OBJECTIVE/BACKGROUND: To investigate experimentally the arterial wall/device compliance mismatch of four stent-graft devices and a multilayer flow modulator within the supra- and infrarenal locations for the treatment of abdominal aortic aneurysms (AAA). METHODS: Five devices (MFM, EndurantII, Excluder, Zenith, and Fortron) were tested under physiological flow conditions within a flow simulator system comprising of a patient-specific thin-walled flexible AAA perfusion model with replicated intraluminal thrombus, supported by the spinal column. Devices were submitted to circumferential force tests and implanted in the perfusion model for circumferential arterial pressure/diameter measurements. Parameters, including radial resistive force, supra-/infrarenal compliance, pulsatile arterial energy loss (PAEL), pulse wave velocity (PWV), and wave reflection coefficient (Γ), were computed to characterise the devices' performance. RESULTS: The Zenith and EndurantII devices had the highest radial resistive force (up to 3 N/cm), while the Fortron device had the lowest (0.11 N/cm). Supra- and infrarenal compliance varied between 6.9-5.1 × 10(-4)/mmHg and 4.8-5.4 × 10(-4)/mmHg, respectively. Two devices (EndurantII and Excluder) significantly decreased infrarenal compliance by 13-26% (p < .001). Four devices increased the PAEL by 13-44% (p < .006). The PWV ranged from 10.9 m/s (MFM; p = .164) to 15.1 m/s (EndurantII; p < .001). There was an increase of 8-238% (p < .001) in the reflection coefficient for all devices. CONCLUSION: Commercially available endovascular devices lower the aortic wall compliance after implantation. The MFM was found to be the most compliant in the suprarenal region, while the Fortron device was the most compliant in the infrarenal region. Choosing the most compliant devices for treating AAAs produces positive gains in the aortic elastic recoil, thus minimising the device related complications.

Injectate spread following ultrasound-guided lateral to medial approach for dual transversus abdominis plane blocks.

BACKGROUND: Bilateral dual transversus abdominis plane (BD-TAP) injections were devised to cover the T7-8 and L1 dermatomes, which are usually spared with classical and mid-axillary TAP injections. The purpose of this study was to delineate the vertical and lateral extent of injectate spread following a lateral to medial approach for TAP injections in embalmed cadavers. METHODS: Ultrasound-guided subcostal and lateral TAP injections were performed on nine embalmed cadavers using 30 ml of 0.5% methylcellulose (20 ml for subcostal and 10 ml for lateral injections) with a 12-cm Tuohy needle in the first six cadavers (nine hemi-abdomens). Vertical extent and the medial to lateral extent of the dye spread were recorded after dissections of the abdominal wall. In a pilot of three cadavers not receiving TAP injections, anatomical impediments to proximal injectate spread were explored separately. RESULTS: The vertical spread of injectate was T7-L1 (n = 2/9), T8-L1 (n = 5/9) and T9-L1 (n = 2/9). None of the TAP injections extended beyond the mid-axillary line. No anatomical impediments for the flow of injectate to the T7 or T8 intercostal nerves were found at the level of the interdigitations of the transversus abdominis muscle and diaphragm. CONCLUSION: A lateral to medial approach for TAP injection resulted in spread of the injectate ranging from T7/8-L1 dermatomes in the majority of the hemi-abdomens. Subcostal and lateral TAP injections do not cover the lateral cutaneous branches of the segmental nerves.

Femoral hernias in the pediatric patient: a case report and review of the literature.

We report a case of a femoral hernia in a 9-year-old male. Femoral hernias in children are rare and a diagnostic challenge. Definitive treatment is with surgical repair.