Publications by authors named "John Ford"

181 Publications

A customizable aluminum compensator system for total body irradiation.

J Appl Clin Med Phys 2021 Aug 25. Epub 2021 Aug 25.

Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.

Purpose: To develop a simplified aluminum compensator system for total body irradiation (TBI) that is easy to assemble and modify in a short period of time for customized patient treatments.

Methods: The compensator is composed of a combination of 0.3 cm thick aluminum bars, two aluminum T-tracks, spacers, and metal bolts. The system is mounted onto a plexiglass block tray. The design consists of 11 fixed sectors spanning from the patient's head to feet. The outermost sectors utilize 7.6 cm wide aluminum bars, while the remaining sectors use 2.5 cm wide aluminum bars. There is a magnification factor of 5 from the compensator to the patient treatment plane. Each bar of aluminum is interconnected at each adjacent sector with a tongue and groove arrangement and fastened to the T-track using a metal washer, bolt, and nut. Inter-bar leakage of the compensator was tested using a water tank and diode. End-to-end measurements were performed with an ion chamber in a solid water phantom and also with a RANDO phantom using internal and external optically stimulated luminescent detectors (OSLDs). In-vivo patient measurements from the first 20 patients treated with this aluminum compensator were compared to those from 20 patients treated with our previously used lead compensator system.

Results: The compensator assembly time was reduced to 20-30 min compared to the 2-4 h it would take with the previous lead design. All end-to-end measurements were within 10% of that expected. The median absolute in-vivo error for the aluminum compensator was 3.7%, with 93.8% of measurements being within 10% of that expected. The median error for the lead compensator system was 5.3%, with 85.1% being within 10% of that expected.

Conclusion: This design has become the standard compensator at our clinic. It allows for quick assembly and customization along with meeting the Task Group 29 recommendations for dose uniformity.
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http://dx.doi.org/10.1002/acm2.13393DOI Listing
August 2021

Inequalities in the distribution of the general practice workforce in England: a practice-level longitudinal analysis.

BJGP Open 2021 Aug 17. Epub 2021 Aug 17.

Clinical Lecturer in Public Health, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Background: In England, demand for primary care services is increasing and GP shortages are widespread. Recently introduced primary care networks (PCNs) aim to expand the use of additional practice-based roles such as physician associates (PAs), pharmacists, paramedics, and others through financial incentives for recruitment of these roles. Inequalities in general practice, including additional roles, have not been examined in recent years, which is a meaningful gap in the literature. Previous research has found that workforce inequalities are associated with health outcome inequalities.

Aim: To examine recent trends in general practice workforce inequalities.

Design & Setting: A longitudinal study using quarterly General Practice Workforce datasets from 2015-2020 in England.

Method: The slope indices of inequality (SIIs) for GPs, nurses, total direct patient care (DPC) staff, PAs, pharmacists, and paramedics per 10 000 patients were calculated quarterly, and plotted over time, with and without adjustment for patient need.

Results: Fewer GPs, total DPC staff, and paramedics per 10 000 patients were employed in more deprived areas. Conversely, more PAs and pharmacists per 10 000 patients were employed in more deprived areas. With the exception of total DPC staff, these observed inequalities widened over time. The unadjusted analysis showed more nurses per 10 000 patients employed in more deprived areas. These values were not significant after adjustment but approached a more equal or pro-poor distribution over time.

Conclusion: Significant workforce inequalities exist and are even increasing for several key general practice roles, with workforce shortages disproportionately affecting more deprived areas. Policy solutions are urgently needed to ensure an equitably distributed workforce and reduce health inequities.
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http://dx.doi.org/10.3399/BJGPO.2021.0066DOI Listing
August 2021

Development and Pilot Implementation of a Remote Monitoring System for Acute Toxicity Using Electronic Patient-Reported Outcomes for Patients Undergoing Radiation Therapy for Breast Cancer.

Int J Radiat Oncol Biol Phys 2021 Jul 24. Epub 2021 Jul 24.

Departments of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York; Center for Health Policy and Outcomes, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Purpose: We aimed to develop and study the implementation of a remote system for toxicity assessment and management of acute side effects of breast radiation using electronic patient-reported outcomes (ePROs).

Methods And Materials: A response-adapted Patient-Reported Outcomes Common Terminology Criteria for Adverse Events-based assessment for breast radiation toxicity was administered weekly during and for 8 weeks after radiation from June 2019 to July 2020. The care team received alerts when "severe" symptoms were reported by patients, who were then contacted. Treatment, clinic, and sociodemographic characteristics were abstracted from patient records. A subsample of patients and care team members was qualitatively interviewed at follow-up.

Results: Overall, 5787 assessments were sent to 678 patients, of whom 489 (72%) completed 2607 assessments (45%). Moderate or greater toxicity was reported by 419 responders (86%; 95% CI, 82%-89%). Clinician alerts for severe toxicity were generated for 264 assessments among 139 unique patients, of which 83% occurred posttreatment. The proportion of surveys that prompted an alert was significantly higher after treatment (219 [13%]) than during treatment (45 [5%]) (P < .001). Survey completion rates in the posttreatment period were higher among patients undergoing partial breast irradiation than postmastectomy radiation (incidence rate ratio, 0.70; 95% CI, 0.60-0.81) (P < .001) despite these patients experiencing less severe toxicity. Interviews (15) found that patients had a positive experience with ePROs, although many thought the primary purpose was for research rather than symptom management.

Conclusions: With the majority of toxicity occurring after breast radiation has ended, remote symptom monitoring with ePROs appears to fill a gap in clinical practice, particularly for patients undergoing shorter courses of radiation. It is important to properly onboard patients and explain that the purpose of ePROs is to aid clinical care. Further research is needed to determine whether the costs associated with ePROs can be offset by reducing routine clinic visits and whether this approach is acceptable and appropriate.
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http://dx.doi.org/10.1016/j.ijrobp.2021.07.1692DOI Listing
July 2021

Reducing inequality in avoidable emergency admissions: Case studies of local health care systems in England using a realist approach.

J Health Serv Res Policy 2021 Jul 21:13558196211021618. Epub 2021 Jul 21.

Professor, Centre for Health Economics, University of York, UK.

Objective: People in disadvantaged areas are more likely to have an avoidable emergency hospital admission. Socio-economic inequality in avoidable emergency hospital admissions is monitored in England. Our aim was to inform local health care purchasing and planning by identifying recent health care system changes (or other factors), as reported by local health system leaders, that might explain narrowing or widening trends.

Methods: Case studies were undertaken in one pilot and at five geographically distinct local health care systems (Clinical Commissioning Groups, CCGs), identified as having consistently increasing or decreasing inequality. Local settings were explored through discussions with CCG officials and stakeholders to identify potential local determinants. Data were analysed using a realist evaluation approach to generate context-mechanism-outcome (CMO) configurations.

Results: Of the five geographically distinct CCGs, two had narrowing inequality, two widening, and one narrowing inequality, which widened during the project. None of the CCGs had designed a large-scale package of service changes with the explicit aim of reducing socio-economic inequality in avoidable emergency admissions, and local decision makers were unfamiliar with their own trends. Potential primary and community care determinants included: workforce, case finding and exclusion, proactive care co-ordination for patients with complex needs, and access and quality. Potential commissioning determinants included: data use and incentives, and targeting of services. Other potential determinants included changes in care home services, national A&E targets, and wider issues - such as public services financial constraints, residential gentrification, and health care expectations.

Conclusions: We did not find any bespoke initiatives that explained the inequality trends. The trends were more likely due to an interplay of multiple health care and wider system factors. Local decision makers need greater awareness, understanding and support to interpret, use and act upon inequality indicators. They are unlikely to find simple, cheap interventions to reduce inequalities in avoidable emergency admissions. Rather, long-term multifaceted interventions are required that embed inequality considerations into mainstream decision making.
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http://dx.doi.org/10.1177/13558196211021618DOI Listing
July 2021

Transforming health systems to reduce health inequalities.

Future Healthc J 2021 Jul;8(2):e204-e209

University of Cambridge, Cambridge, UK.

Never before in history have we had the data to track such a rapid increase in inequalities. With changes imminent in healthcare and public health organisational landscape in England and health inequalities high on the policy agenda, we have an opportunity to redouble efforts to reduce inequalities. In this article, we argue that health inequalities need re-framing to encompass the breadth of disadvantage and difference between healthcare and health outcome inequalities. Second, there needs to be a focus on long-term organisational change to ensure equity is considered in all decisions. Third, actions need to prioritise the fundamental redistribution of resources, funding, workforce, services and power. Reducing inequalities can involve unpopular and difficult decisions. Physicians have a particular role in society and can support evidenced-based change across practice and the system at large. If we do not act now, then when?
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http://dx.doi.org/10.7861/fhj.2021-0018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285147PMC
July 2021

Reducing health inequalities through general practice: protocol for a realist review (EQUALISE).

BMJ Open 2021 06 15;11(6):e052746. Epub 2021 Jun 15.

Nuffield Department of Primary Care Health Sciences, Oxford University, Oxford, UK.

Introduction: Healthcare organisations recognise the moral imperative to address inequalities in health outcomes but often lack an understanding of which types of interventions are likely to reduce them. This realist review will examine the existing evidence on the types of interventions or aspects of routine care in general practice that are likely to decrease or increase health inequalities (ie, inequality-generating interventions) across cardiovascular disease, cancer, diabetes and chronic obstructive pulmonary disease.

Methods And Analysis: Our realist review will follow Pawson's five iterative stages. We will start by developing an initial programme theory based on existing theories and discussions with stakeholders. To navigate the large volume of literature, we will access the primary studies through the identification of published systematic reviews of interventions delivered in general practice across the four key conditions. We will examine the primary studies included within each systematic review to identify those reporting on inequalities across PROGRESS-Plus categories. We will collect data on a range of clinical outcomes including prevention, diagnosis, follow-up and treatment. The data will be synthesised using a realist logic of analysis. The findings will be a description and explanation of the general practice interventions which are likely to increase or decrease inequalities across the major conditions.

Ethics And Dissemination: Ethics approval is not required because this study does not include any primary research. The findings will be integrated into a series of guiding principles and a toolkit for healthcare organisations to reduce health inequalities. Findings will be disseminated through peer-reviewed publications, conference presentations and user-friendly summaries.

Prospero Registration Number: CRD42020217871.
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http://dx.doi.org/10.1136/bmjopen-2021-052746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208022PMC
June 2021

Prostate Cancer Targeted X-Ray Fluorescence Imaging via Gold Nanoparticles Functionalized With Prostate-Specific Membrane Antigen (PSMA).

Int J Radiat Oncol Biol Phys 2021 09 6;111(1):220-232. Epub 2021 May 6.

Department of Radiation Oncology, Miller School of Medicine, University of Miami, Miami, Florida.

Purpose: The gold nanoparticle (GNP) as a promising theranostic probe has been increasingly studied. The tumor-targeting efficiency of GNPs is crucial to increase the therapeutic ratio. In this study, we developed PSMA-targeted GNPs to enhance GNP uptake in prostate cancer and developed an x-ray fluorescence imaging system to noninvasively monitor and assess GNP delivery.

Methods And Materials: For targeted therapy of prostate cancer, anti-prostate-specific membrane antigen (PSMA) antibodies were conjugated onto PEGylated GNPs through 1-ethyl-3-(-3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) (EDC/NHS) chemistry. In vivo imaging was implemented using an in-house-developed dual-modality computed tomography (CT) and x-ray fluorescence CT (XFCT) system on mice bearing subcutaneous LNCaP prostate tumors. After intravenous administration of GNPs (15 mg/mL, 200 μL), the x-ray fluorescence signals from the tumor were collected at various time points (5 minutes to approximately 30 hours) for GNP pharmacokinetics analysis. At 24 hours after administration, x-ray fluorescence projection (XRFproj) and XFCT imaging were conducted to evaluate the prostate tumor uptake of active- and passive-targeting GNPs. Inductively coupled plasma mass spectrometry analysis was adopted as a benchmark to verify the quantification accuracy of XRFproj/XFCT imaging.

Results: Fluorescence microscopic imaging confirmed the enhanced (approximately 4 times) targeting efficiency of PSMA-targeted GNPs in vitro. The pharmacokinetics analysis showed enhanced tumor uptake/retention of PSMA-targeted GNPs and revealed that the peak tumor accumulation appeared at approximately 24 hours after intravenous administration. Both XRFproj and XFCT imaging presented their accuracy in quantifying GNPs within tumors noninvasively. Moreover, XFCT imaging verified its unique capabilities to simultaneously determine the heterogeneous spatial distribution and the concentration of GNPs within tumors in vivo.

Conclusions: In conjunction with PSMA-targeted GNPs, XRFproj/XFCT would be a highly sensitive tool for targeted imaging of prostate cancer, benefiting the elucidation of mechanisms of GNP-assisted prostate-cancer therapy.
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http://dx.doi.org/10.1016/j.ijrobp.2021.04.032DOI Listing
September 2021

A deepening understanding of animal culture suggests lessons for conservation.

Proc Biol Sci 2021 04 21;288(1949):20202718. Epub 2021 Apr 21.

Sea Mammal Research Unit, School of Biology, University of St Andrews, St Andrews KY16 8LB, UK.

A key goal of conservation is to protect biodiversity by supporting the long-term persistence of viable, natural populations of wild species. Conservation practice has long been guided by genetic, ecological and demographic indicators of risk. Emerging evidence of animal culture across diverse taxa and its role as a driver of evolutionary diversification, population structure and demographic processes may be essential for augmenting these conventional conservation approaches and decision-making. Animal culture was the focus of a ground-breaking resolution under the Convention on the Conservation of Migratory Species of Wild Animals (CMS), an international treaty operating under the UN Environment Programme. Here, we synthesize existing evidence to demonstrate how social learning and animal culture interact with processes important to conservation management. Specifically, we explore how social learning might influence population viability and be an important resource in response to anthropogenic change, and provide examples of how it can result in phenotypically distinct units with different, socially learnt behavioural strategies. While identifying culture and social learning can be challenging, indirect identification and parsimonious inferences may be informative. Finally, we identify relevant methodologies and provide a framework for viewing behavioural data through a cultural lens which might provide new insights for conservation management.
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http://dx.doi.org/10.1098/rspb.2020.2718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059593PMC
April 2021

MR-Guided Radiotherapy for Brain and Spine Tumors.

Front Oncol 2021 8;11:626100. Epub 2021 Mar 8.

Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, United States.

MRI is the standard modality to assess anatomy and response to treatment in brain and spine tumors given its superb anatomic soft tissue contrast (e.g., T1 and T2) and numerous additional intrinsic contrast mechanisms that can be used to investigate physiology (e.g., diffusion, perfusion, spectroscopy). As such, hybrid MRI and radiotherapy (RT) devices hold unique promise for Magnetic Resonance guided Radiation Therapy (MRgRT). In the brain, MRgRT provides daily visualizations of evolving tumors that are not seen with cone beam CT guidance and cannot be fully characterized with occasional standalone MRI scans. Significant evolving anatomic changes during radiotherapy can be observed in patients with glioblastoma during the 6-week fractionated MRIgRT course. In this review, a case of rapidly changing symptomatic tumor is demonstrated for possible therapy adaptation. For stereotactic body RT of the spine, MRgRT acquires clear isotropic images of tumor in relation to spinal cord, cerebral spinal fluid, and nearby moving organs at risk such as bowel. This visualization allows for setup reassurance and the possibility of adaptive radiotherapy based on anatomy in difficult cases. A review of the literature for MR relaxometry, diffusion, perfusion, and spectroscopy during RT is also presented. These techniques are known to correlate with physiologic changes in the tumor such as cellularity, necrosis, and metabolism, and serve as early biomarkers of chemotherapy and RT response correlating with patient survival. While physiologic tumor investigations during RT have been limited by the feasibility and cost of obtaining frequent standalone MRIs, MRIgRT systems have enabled daily and widespread physiologic measurements. We demonstrate an example case of a poorly responding tumor on the 0.35 T MRIgRT system with relaxometry and diffusion measured several times per week. Future studies must elucidate which changes in MR-based physiologic metrics and at which timepoints best predict patient outcomes. This will lead to early treatment intensification for tumors identified to have the worst physiologic responses during RT in efforts to improve glioblastoma survival.
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http://dx.doi.org/10.3389/fonc.2021.626100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982530PMC
March 2021

Inequalities in general practice remote consultations: a systematic review.

BJGP Open 2021 Jun 30;5(3). Epub 2021 Jun 30.

Clinical Lecturer in Public Health, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

Background: COVID-19 has led to rapid and widespread use of remote consultations in general practice, but the health inequalities impact remains unknown.

Aim: To explore the impact of remote consultations in general practice, compared to face-to-face consultations, on utilisation and clinical outcomes across socioeconomic and disadvantaged groups.

Design & Setting: Systematic review.

Method: The authors undertook an electronic search of MEDLINE, EMBASE, and Web of Science from inception to June 2020. The study included studies that compared remote consultations to face-to-face consultations in primary care and reported outcomes by PROGRESS Plus criteria. Risk of bias was assessed using ROBINS-I. Data were synthesised narratively.

Results: Based on 13 studies that explored telephone and internet-based consultations, this review found that telephone consultations were used by younger people of working age, the very old, and non-immigrants, with internet-based consultations more likely to be used by younger people. Women consistently used more remote forms of consulting than men. Socioeconomic and ethnicity findings were mixed, with weak evidence that patients from more affluent areas were more likely to use internet-based communication. Remote consultations appeared to help patients with opioid dependence remain engaged with primary care. No studies reported on the impact on quality of care or clinical outcomes.

Conclusion: Remote consultations in general practice are likely to be used more by younger, working people, non-immigrants, older patients, and women, with internet-based consultations more by younger, affluent, and educated groups. Widespread use of remote consultations should be treated with caution until the inequalities impact on clinical outcomes and quality of care is known.
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http://dx.doi.org/10.3399/BJGPO.2021.0040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278507PMC
June 2021

Vaccination against COVID-19 and inequalities - Avoiding making a bad situation worse.

Public Health Pract (Oxf) 2021 Nov 3;2:100101. Epub 2021 Mar 3.

School of Health and Related Research (ScHARR), The University of Sheffield, Sheffield, UK.

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http://dx.doi.org/10.1016/j.puhip.2021.100101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927589PMC
November 2021

Repeatability of CBCT radiomic features and their correlation with CT radiomic features for prostate cancer.

Med Phys 2021 May 16;48(5):2386-2399. Epub 2021 Mar 16.

Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL, USA.

Purpose: Radiomic features of cone-beam CT (CBCT) images have potential as biomarkers to predict treatment response and prognosis for patients of prostate cancer. Previous studies of radiomic feature analysis for prostate cancer were assessed in a variety of imaging modalities, including MRI, PET, and CT, but usually limited to a pretreatment setting. However, CBCT images may provide an opportunity to capture early morphological changes to the tumor during treatment that could lead to timely treatment adaptation. This work investigated the quality of CBCT-based radiomic features and their relationship with reconstruction methods applied to the CBCT projections and the preprocessing methods used in feature extraction. Moreover, CBCT features were correlated with planning CT (pCT) features to further assess the viability of CBCT radiomic features.

Methods: The quality of 42 CBCT-based radiomic features was assessed according to their repeatability and reproducibility. Repeatability was quantified by correlating radiomic features between 20 CBCT scans that also had repeated scans within 15 minutes. Reproducibility was quantified by correlating radiomic features between the planning CT (pCT) and the first fraction CBCT for 20 patients. Concordance correlation coefficients (CCC) of radiomic features were used to estimate the repeatability and reproducibility of radiomic features. The same patient dataset was assessed using different reconstruction methods applied to the CBCT projections. CBCT images were generated using 18 reconstruction methods using iterative (iCBCT) and standard (sCBCT) reconstructions, three convolution filters, and five noise suppression filters. Eighteen preprocessing settings were also considered.

Results: Overall, CBCT radiomic features were more repeatable than reproducible. Five radiomic features are repeatable in > 97% of the reconstruction and preprocessing methods, and come from the gray-level size zone matrix (GLSZM), neighborhood gray-tone difference matrix (NGTDM), and gray-level-run length matrix (GLRLM) radiomic feature classes. These radiomic features were reproducible in > 9.8% of the reconstruction and preprocessing methods. Noise suppression and convolution filter smoothing increased radiomic features repeatability, but decreased reproducibility. The top-repeatable iCBCT method (iCBCT-Sharp-VeryHigh) is more repeatable than the top-repeatable sCBCT method (sCBCT-Smooth) in 64% of the radiomic features.

Conclusion: Methods for reconstruction and preprocessing that improve CBCT radiomic feature repeatability often decrease reproducibility. The best approach may be to use methods that strike a balance repeatability and reproducibility such as iCBCT-Sharp-VeryLow-1-Lloyd-256 that has 17 repeatable and eight reproducible radiomic features. Previous radiomic studies that only used pCT radiomic features have generated prognostic models of prostate cancer outcome. Since our study indicates that CBCT radiomic features correlated well with a subset of pCT radiomic features, one may expect CBCT radiomics to also generate prognostic models for prostate cancer.
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http://dx.doi.org/10.1002/mp.14787DOI Listing
May 2021

Making healthcare accessible for single adults with complex needs experiencing long-term homelessness: A realist evaluation protocol.

HRB Open Res 2020 21;3:73. Epub 2021 Jan 21.

Centre for Health Policy and Management, Trinity College Dublin, Dublin 2, Dublin, Ireland.

Over the last several years, homelessness has increased in Ireland and across Europe. Rates have recently declined since the coronavirus disease 2019 (COVID-19) pandemic, but it is unclear whether emergency housing measures will remain in place permanently. Populations experiencing long-term homelessness face a higher burden of multi-morbidity at an earlier age than housed populations and have poorer health outcomes. However, this population also has more difficulty accessing appropriate health services. A realist review by the authors found that important health system contexts which impact access are resourcing, training, funding cycles, health system fragmentation, health system goals, how care is organised, culture, leadership and flexibility of care delivery. Using a realist evaluation approach, this research will explore and refine key system-level factors, highlighted in our realist review, in a local health care system. The aim of this study is to understand how funding procedures and health system performance management impact service settings, staff, providers and their ability to make services accessible to populations experiencing homelessness. : A realist evaluation will be undertaken to explain how funding and health system performance management impact healthcare accessibility for populations experiencing homelessness. Data will be collected using qualitative and realist interview techniques and focus group methodology. Secondary data such as policy documents and budgets will utilised. The analysis will follow Pawson and Tilley's iterative phases starting with building an Initial programme theory, then data collection, data analysis, synthesis and finally building a refined programme theory. : Building on a realist review conducted by the same research team, this study will further test and refine findings that explain how health system factors impact healthcare accessibility for populations experiencing homelessness. The study has the potential to inform policy makers, health planners and managers of contextual factors that can be modified to increase healthcare accessibility.
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http://dx.doi.org/10.12688/hrbopenres.13154.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836031PMC
January 2021

Detecting turnover among complex communities using null models: a case study with sky-island haemosporidian parasites.

Oecologia 2021 Feb 23;195(2):435-451. Epub 2021 Jan 23.

Museum of Southwestern Biology and Department of Biology, University of New Mexico, Albuquerque, NM, USA.

Turnover in species composition between sites, or beta diversity, is a critical component of species diversity that is typically influenced by geography, environment, and biotic interactions. Quantifying turnover is particularly challenging, however, in multi-host, multi-parasite assemblages where undersampling is unavoidable, resulting in inflated estimates of turnover and uncertainty about its spatial scale. We developed and implemented a framework using null models to test for community turnover in avian haemosporidian communities of three sky islands in the southwestern United States. We screened 776 birds for haemosporidian parasites from three genera (Parahaemoproteus, Plasmodium, and Leucocytozoon) by amplifying and sequencing a mitochondrial DNA barcode. We detected infections in 280 birds (36.1%), sequenced 357 infections, and found a total of 99 parasite haplotypes. When compared to communities simulated from a regional pool, we observed more unique, single-mountain haplotypes and fewer haplotypes shared among three mountain ranges than expected, indicating that haemosporidian communities differ to some degree among adjacent mountain ranges. These results were robust even after pruning datasets to include only identical sets of host species, and they were consistent for two of the three haemosporidian genera. The two more distant mountain ranges were more similar to each other than the one located centrally, suggesting that the differences we detected were due to stochastic colonization-extirpation dynamics. These results demonstrate that avian haemosporidian communities of temperate-zone forests differ on relatively fine spatial scales between adjacent sky islands. Null models are essential tools for testing the spatial scale of turnover in complex, undersampled, and poorly known systems.
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http://dx.doi.org/10.1007/s00442-021-04854-6DOI Listing
February 2021

Omega-3 fatty acid modulation of serum and osteocyte tumor necrosis factor-α in adult mice exposed to ionizing radiation.

J Appl Physiol (1985) 2021 03 7;130(3):627-639. Epub 2021 Jan 7.

Departments of Health and Kinesiology, Texas A&M University, College Station, Texas.

Chronic inflammation leads to bone loss and fragility. Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) consistently promote bone resorption. Dietary modulation of proinflammatory cytokines is an accepted therapeutic approach to treat chronic inflammation, including that induced by space-relevant radiation exposure. As such, these studies were designed to determine whether an anti-inflammatory diet, high in omega-3 fatty acids, could reduce radiation-mediated bone damage via reductions in the levels of inflammatory cytokines in osteocytes and serum. Lgr5-EGFP C57BL/6 mice were randomized to receive diets containing fish oil and pectin (FOP; high in omega-3 fatty acids) or corn oil and cellulose (COC; high in omega-6 fatty acids) and then acutely exposed to 0.5-Gy Fe or 2.0-Gy gamma-radiation. Mice fed the FOP diet exhibited consistent reductions in serum TNF-α in the Fe experiment but not the gamma-experiment. The percentage osteocytes (%Ot) positive for TNF-α increased in gamma-exposed COC, but not FOP, mice. Minimal changes in %Ot positive for sclerostin were observed. FOP mice exhibited modest improvements in several measures of cancellous microarchitecture and volumetric bone mineral density (BMD) postexposure to Fe and gamma-radiation. Reduced serum TNF-α in FOP mice exposed to Fe was associated with either neutral or modestly positive changes in bone structural integrity. Collectively, these data are generally consistent with previous findings that dietary intake of omega-3 fatty acids may effectively mitigate systemic inflammation after acute radiation exposure and facilitate maintenance of BMD during spaceflight in humans. This is the first investigation, to our knowledge, to test the impact of a diet high in omega-3 fatty acids on multiple bone structural and biological outcomes following space-relevant radiation exposure. Novel in biological outcomes is the assessment of osteocyte responses to this stressor. These data also add to the growing evidence that low-dose exposures to even high-energy ion species like Fe may have neutral or even small positive impacts on bone.
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http://dx.doi.org/10.1152/japplphysiol.00848.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988793PMC
March 2021

Inequalities in mental health: predictive processing and social life.

Curr Opin Psychiatry 2021 03;34(2):171-176

Department of Psychiatry, University of Cambridge, Herchel Smith Building, Addenbrooke's Hospital, Cambridge, UK, Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK, Wellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.

Purpose Of Review: The paper applies recent conceptualisations of predictive processing to the understanding of inequalities in mental health.

Recent Findings: Social neuroscience has developed important ideas about the way the brain models the external world, and how the interface between cognitive and cultural processes interacts. These resonate with earlier concepts from cybernetics and sociology. These approaches could be applied to understanding some of the dynamics leading to the patterning of mental health problems in populations.

Summary: The implications for practice are the way such thinking might help illuminate how we think and act, and how these are anchored in the social world.
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http://dx.doi.org/10.1097/YCO.0000000000000680DOI Listing
March 2021

Pathology findings and correlation with body condition index in stranded killer whales (Orcinus orca) in the northeastern Pacific and Hawaii from 2004 to 2013.

PLoS One 2020 2;15(12):e0242505. Epub 2020 Dec 2.

The SeaDoc Society, Karen C. Drayer Wildlife Health Center - Orcas Island Office, UC Davis School of Veterinary Medicine, Eastsound, Washington, United States of America.

Understanding health and mortality in killer whales (Orcinus orca) is crucial for management and conservation actions. We reviewed pathology reports from 53 animals that stranded in the eastern Pacific Ocean and Hawaii between 2004 and 2013 and used data from 35 animals that stranded from 2001 to 2017 to assess association with morphometrics, blubber thickness, body condition and cause of death. Of the 53 cases, cause of death was determined for 22 (42%) and nine additional animals demonstrated findings of significant importance for population health. Causes of calf mortalities included infectious disease, nutritional, and congenital malformations. Mortalities in sub-adults were due to trauma, malnutrition, and infectious disease and in adults due to bacterial infections, emaciation and blunt force trauma. Death related to human interaction was found in every age class. Important incidental findings included concurrent sarcocystosis and toxoplasmosis, uterine leiomyoma, vertebral periosteal proliferations, cookiecutter shark (Isistius sp.) bite wounds, excessive tooth wear and an ingested fish hook. Blubber thickness increased significantly with body length (all p < 0.001). In contrast, there was no relationship between body length and an index of body condition (BCI). BCI was higher in animals that died from trauma. This study establishes a baseline for understanding health, nutritional status and causes of mortality in stranded killer whales. Given the evidence of direct human interactions on all age classes, in order to be most successful recovery efforts should address the threat of human interactions, especially for small endangered groups of killer whales that occur in close proximity to large human populations, interact with recreational and commercial fishers and transit established shipping lanes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242505PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710042PMC
January 2021

Impact of quantization algorithm and number of gray level intensities on variability and repeatability of low field strength magnetic resonance image-based radiomics texture features.

Phys Med 2020 Dec 12;80:209-220. Epub 2020 Nov 12.

Department of Radiation Oncology, University of Miami Miller School of Medicine, 1475 NW 12(th) Ave, Miami, FL 33136, USA. Electronic address:

Purpose: The purpose of this work was to investigate the impact of quantization preprocessing parameter selection on variability and repeatability of texture features derived from low field strength magnetic resonance (MR) images.

Methods: Texture features were extracted from low field strength images of a daily image QA phantom with four texture inserts. Feature variability over time was quantified using all combinations of three quantization algorithms and four different numbers of gray level intensities. In addition, texture features were extracted using the same combinations from the low field strength MR images of the gross tumor volume (GTV) and left kidney of patients with repeated set up scans. The impact of region of interest (ROI) preprocessing on repeatability was investigated with a test-retest study design.

Results: The phantom ROIs quantized to 64 Gy level intensities using the histogram equalization method resulted in the greatest number of features with the least variability. There was no clear method that resulted in the highest repeatability in the GTV or left kidney. However, eight texture features extracted from the GTV were repeatable regardless of ROI processing combination.

Conclusion: Low field strength MR images can provide a stable basis for texture analysis with ROIs quantized to 64 Gy levels using histogram equalization, but there is no clear optimal combination for repeatability.
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http://dx.doi.org/10.1016/j.ejmp.2020.10.029DOI Listing
December 2020

Margin verification for hypofractionated prostate radiotherapy using a novel dose accumulation workflow and iterative CBCT.

Phys Med 2020 Sep 28;77:154-159. Epub 2020 Aug 28.

Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1475 NW 12th Ave., Miami, FL 33136, United States.

Purpose: Hypofractionated radiotherapy for prostate cancer reduces the inconvenience of an extended treatment course but the appropriate treatment margin to ensure tumor control while minimizing toxicity is not standardized. Using a novel dose accumulation workflow with iterative CBCT (iCBCT) images, we were able to validate treatment margins.

Methods: Sixteen patients treated to the prostate on a hypofractionated clinical trial were selected. Prescription dose was 3625 cGy to > 95% of the PTV in 5 fractions with a boost to 4000 cGy to the high risk GTV (if applicable). PTV margin expansion was 5 mm isotropic except 3 mm posterior, no margin for the GTV. Daily iCBCT images were obtained while practicing strict bladder and rectal filling protocols. Using a novel adaptive dose accumulation workflow, synthetic CTs were created and the daily delivered dose was recalculated. The daily dose distributions were accumulated and target coverage and organ dose were assessed.

Results: Although the PTV coverage dropped for the accumulated dose, the prostate coverage was not compromised. The differences in bladder and anorectum dose were not significantly different. Four patients received a boost to the GTV and a significant decrease in coverage was noted in the accumulated dose.

Conclusions: The novel dose accumulation workflow demonstrated that daily iCBCT images can be used for dose accumulation. We found that our clinical treatment margins resulted in adequate dose to the prostate while sparing OARs. If the goal is to deliver the full dose to an intra-prostatic GTV, a margin may be appropriate.
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http://dx.doi.org/10.1016/j.ejmp.2020.08.008DOI Listing
September 2020

The role of radiomics in prostate cancer radiotherapy.

Strahlenther Onkol 2020 Oct 21;196(10):900-912. Epub 2020 Aug 21.

Department of Radiation Oncology, University of Miami Miller School of Medicine, 1121 NW 14th St, 33136, Miami, FL, USA.

"Radiomics," as it refers to the extraction and analysis of a large number of advanced quantitative radiological features from medical images using high-throughput methods, is perfectly suited as an engine for effectively sifting through the multiple series of prostate images from before, during, and after radiotherapy (RT). Multiparametric (mp)MRI, planning CT, and cone beam CT (CBCT) routinely acquired throughout RT and the radiomics pipeline are developed for extraction of thousands of variables. Radiomics data are in a format that is appropriate for building descriptive and predictive models relating image features to diagnostic, prognostic, or predictive information. Prediction of Gleason score, the histopathologic cancer grade, has been the mainstay of the radiomic efforts in prostate cancer. While Gleason score (GS) is still the best predictor of treatment outcome, there are other novel applications of quantitative imaging that are tailored to RT. In this review, we summarize the radiomics efforts and discuss several promising concepts such as delta-radiomics and radiogenomics for utilizing image features for assessment of the aggressiveness of prostate cancer and its outcome. We also discuss opportunities for quantitative imaging with the advance of instrumentation in MRI-guided therapies.
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http://dx.doi.org/10.1007/s00066-020-01679-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545508PMC
October 2020

Tn-Seq Analysis Identifies Genes Important for Yersinia pestis Adherence during Primary Pneumonic Plague.

mSphere 2020 08 5;5(4). Epub 2020 Aug 5.

Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

Following inhalation, rapidly colonizes the lung to establish infection during primary pneumonic plague. Although several adhesins have been identified in spp., the factors mediating early adherence in the lung remain unknown. To identify genes important for adherence during primary pneumonic plague, we used transposon insertion sequencing (Tn-seq). Wild-type and capsule mutant (Δ) transposon mutant libraries were serially passaged to enrich for nonadherent mutants in the lung using a mouse model of primary pneumonic plague. Sequencing of the passaged libraries revealed six mutants that were significantly enriched in both the wild-type and Δ backgrounds. The enriched mutants had insertions in genes that encode transcriptional regulators, chaperones, an endoribonuclease, and YPO3903, a hypothetical protein. Using single-strain infections and a transcriptional analysis, we identified a significant role for in adherence in the lung and showed that YPO3903 regulated transcript levels of which encodes a fimbria previously implicated in adherence Deletion of had a minor effect on adherence in the lung, suggesting that YPO3903 regulates other adhesins in addition to By enriching for mutations in genes that regulate the expression or assembly of multiple genes or proteins, we obtained screen results indicating that there may be not just one dominant adhesin but rather several factors that contribute to early adherence during primary pneumonic plague. Colonization of the lung by is a critical first step in establishing infection during primary pneumonic plague, a disease characterized by high lethality. However, the mechanisms by which adheres in the lung after inhalation remain elusive. Here, we used Tn-seq to identify genes important for adherence early during primary pneumonic plague. Our mutant enrichment strategy resulted in the identification of genes important for regulation and assembly of genes and proteins rather than adhesin genes themselves. These results reveal that there may be multiple adhesins or redundancy among adhesins. Identifying the adhesins regulated by the genes identified in our enrichment screen may reveal novel therapeutic targets for preventing adherence and the subsequent development of pneumonic plague.
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http://dx.doi.org/10.1128/mSphere.00715-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407073PMC
August 2020

The COVID-19 pandemic and health inequalities.

J Epidemiol Community Health 2020 11 13;74(11):964-968. Epub 2020 Jun 13.

Population Health Sciences Institute, Newcastle University Institute for Health and Society, Newcastle upon Tyne, UK.

This essay examines the implications of the COVID-19 pandemic for health inequalities. It outlines historical and contemporary evidence of inequalities in pandemics-drawing on international research into the Spanish influenza pandemic of 1918, the H1N1 outbreak of 2009 and the emerging international estimates of socio-economic, ethnic and geographical inequalities in COVID-19 infection and mortality rates. It then examines how these inequalities in COVID-19 are related to existing inequalities in chronic diseases and the social determinants of health, arguing that we are experiencing a It then explores the potential consequences for health inequalities of the lockdown measures implemented internationally as a response to the COVID-19 pandemic, focusing on the likely unequal impacts of the economic crisis. The essay concludes by reflecting on the longer-term public health policy responses needed to ensure that the COVID-19 pandemic does not increase health inequalities for future generations.
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http://dx.doi.org/10.1136/jech-2020-214401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298201PMC
November 2020

The "unknown territory" of goal-setting: Negotiating a novel interactional activity within primary care doctor-patient consultations for patients with multiple chronic conditions.

Soc Sci Med 2020 07 15;256:113040. Epub 2020 May 15.

Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK. Electronic address:

Goal-setting is widely recommended for supporting patients with multiple long-term conditions. It involves a proactive approach to a clinical consultation, requiring doctors and patients to work together to identify patient's priorities, values and desired outcomes as a basis for setting goals for the patient to work towards. Importantly it comprises a set of activities that, for many doctors and patients, represents a distinct departure from a conventional consultation, including goal elicitation, goal-setting and action planning. This indicates that goal-setting is an uncertain interactional space subject to inequalities in understanding and expectations about what type of conversation is taking place, the roles of patient and doctor, and how patient priorities may be configured as goals. Analysing such spaces therefore has the potential for revealing how the principles of goal-setting are realised in practice. In this paper, we draw on Goffman's concept of 'frames' to present an examination of how doctors' and patients' sense making of goal-setting was consequential for the interactions that followed. Informed by Interactional Sociolinguistics, we used conversation analysis methods to analyse 22 video-recorded goal-setting consultations with patients with multiple long-term conditions. Data were collected between 2016 and 2018 in three UK general practices as part of a feasibility study. We analysed verbal and non-verbal actions for evidence of GP and patient framings of consultation activities and how this was consequential for setting goals. We identified three interactional patterns: GPs checking and reframing patients' understanding of the goal-setting consultation, GPs actively aligning with patients' framing of their goal, and patients passively and actively resisting GP framing of the patient goals. These reframing practices provided "telling cases" of goal-setting interactions, where doctors and patients need to negotiate each other's perspectives but also conflicting discourses of patient-centredness, population-based evidence for treating different chronic illnesses and conventional doctor-patient relations.
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http://dx.doi.org/10.1016/j.socscimed.2020.113040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306159PMC
July 2020

Effect of selective I inhibition by XAF-1407 in an equine model of tachypacing-induced persistent atrial fibrillation.

Br J Pharmacol 2020 08 24;177(16):3778-3794. Epub 2020 Jun 24.

Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.

Background And Purpose: Inhibition of the G-protein gated ACh-activated inward rectifier potassium current, I may be an effective atrial selective treatment strategy for atrial fibrillation (AF). Therefore, the anti-arrhythmic and electrophysiological properties of a novel putatively potent and highly specific I inhibitor, XAF-1407 (3-methyl-1-[5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-6-yl]azetidin-3-ol), were characterised for the first time in vitro and investigated in horses with persistent AF.

Experimental Approach: The pharmacological ion channel profile of XAF-1407 was investigated using cell lines expressing relevant ion channels. In addition, eleven horses were implanted with implantable cardioverter defibrillators enabling atrial tachypacing into self-sustained AF. The electrophysiological effects of XAF-1407 were investigated after serial cardioversions over a period of 1 month. Cardioversion success, drug-induced changes of atrial tissue refractoriness, and ventricular electrophysiology were assessed at baseline (day 0) and days 3, 5, 11, 17, and 29 after AF induction.

Key Results: XAF-1407 potently and selectively inhibited K 3.1/3.4 and K 3.4/3.4, underlying the I current. XAF-1407 treatment in horses prolonged atrial effective refractory period as well as decreased atrial fibrillatory rate significantly (~20%) and successfully cardioverted AF, although with a decreasing efficacy over time. XAF-1407 shortened atrioventricular-nodal refractoriness, without effect on QRS duration. QTc prolongation (4%) within 15 min of drug infusion was observed, however, without any evidence of ventricular arrhythmia.

Conclusion And Implications: XAF-1407 efficiently cardioverted sustained tachypacing-induced AF of short duration in horses without notable side effects. This supports I inhibition as a potentially safe treatment of paroxysmal AF in horses, suggesting potential clinical value for other species including humans.
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http://dx.doi.org/10.1111/bph.15100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393200PMC
August 2020

Predictive value of 0.35 T magnetic resonance imaging radiomic features in stereotactic ablative body radiotherapy of pancreatic cancer: A pilot study.

Med Phys 2020 Aug 16;47(8):3682-3690. Epub 2020 May 16.

Department of Radiation Oncology, University of Miami, Miami, FL, 33136, USA.

Purpose: The aim of this study was to evaluate the potential and feasibility of radiomic features extracted from low field strength (0.35 T) magnetic resonance images (MRIs) in predicting treatment response for patients with pancreatic cancer undergoing stereotactic body radiotherapy (SBRT).

Methods: Twenty patients with unresected, non-metastatic pancreatic ductal adenocarcinoma (PDAC) were enrolled, all of whom received neoadjuvant chemotherapy followed by five-fraction MR-guided SBRT with a radiation dose range of 33-50 Gy. For each patient, five daily setup scans were acquired from a hybrid 0.35 T MRI/radiotherapy unit. Tumor heterogeneity quantified with radiomic features extracted from the gross tumor volume (GTV) was averaged over the course of treatment. Random forest (RF) and adaptive least absolute shrinkage and selection operator (LASSO) classification models were constructed to identify radiomics features predictive of treatment response. Predictive capability of the top-performing features was then evaluated using the receiver operating characteristic area under curve (AUC) obtained using leave-one-out cross-validation.

Results: Half of the 20 patients showed response to treatment, defined by tumor regression on histopathology or tumor response on follow-up dynamic contrast-enhanced computed tomography (CT). The most predictive features selected by the RF method were GLCM energy and GLSZM gray-level variance. The RF-based model achieved an AUC = 0.81 with a 95% confidence interval of [0.594 to 1] The LASSO algorithm selected GLCM energy as the only predictive feature, achieving an AUC = 0.81 with 95% confidence interval of [0.596 to 1].

Conclusion: The findings of this study suggest that radiomic features extracted during MR-guided SBRT may contain predictive information about response of PDAC patients to treatment. Using the images acquired during treatment of PDAC patients supports continued expansion of radiomic analysis based on low field strength MR images and may hold the potential for providing timely indications of response to treatment.
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http://dx.doi.org/10.1002/mp.14200DOI Listing
August 2020

The impact of maturation time distributions on the structure and growth of cellular populations.

Math Biosci Eng 2019 12;17(2):1855-1888

Department of Mathematical Sciences, Middle Tennessee State University, MTSU Box 34, Murfreesboro, TN 37132, USA.

Here we study how the structure and growth of a cellular population vary with the distribution of maturation times from each stage. We consider two cell cycle stages. The first represents early G1. The second includes late G1, S, G2, and mitosis. Passage between the two reflects passage of an important cell cycle checkpoint known as the restriction point. We model the population as a system of partial differential equations. After establishing the existence of solutions, we characterize the maturation rates and derive the steady-state age and stage distributions as well as the asymptotic growth rates for models with exponential and inverse Gaussian maturation time distributions. We find that the stable age and stage distributions, transient dynamics, and asymptotic growth rates are substantially different for these two maturation models. We conclude that researchers modeling cellular populations should take care when choosing a maturation time distribution, as the population growth rate and stage structure can be heavily impacted by this choice. Furthermore, differences in the models' transient dynamics constitute testable predictions that can help further our understanding of the fundamental process of cellular proliferation. We hope that our numerical methods and programs will provide a scaffold for future research on cellular proliferation.
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http://dx.doi.org/10.3934/mbe.2020098DOI Listing
December 2019

Postreproductive killer whale grandmothers improve the survival of their grandoffspring.

Proc Natl Acad Sci U S A 2019 Dec 9. Epub 2019 Dec 9.

Department of Biology, The University of York, York YO10 5DD, United Kingdom;

Understanding why females of some mammalian species cease ovulation prior to the end of life is a long-standing interdisciplinary and evolutionary challenge. In humans and some species of toothed whales, females can live for decades after stopping reproduction. This unusual life history trait is thought to have evolved, in part, due to the inclusive fitness benefits that postreproductive females gain by helping kin. In humans, grandmothers gain inclusive fitness benefits by increasing their number of surviving grandoffspring, referred to as the grandmother effect. Among toothed whales, the grandmother effect has not been rigorously tested. Here, we test for the grandmother effect in killer whales, by quantifying grandoffspring survival with living or recently deceased reproductive and postreproductive grandmothers, and show that postreproductive grandmothers provide significant survival benefits to their grandoffspring above that provided by reproductive grandmothers. This provides evidence of the grandmother effect in a nonhuman menopausal species. By stopping reproduction, grandmothers avoid reproductive conflict with their daughters, and offer increased benefits to their grandoffspring. The benefits postreproductive grandmothers provide to their grandoffspring are shown to be most important in difficult times where the salmon abundance is low to moderate. The postreproductive grandmother effect we report, together with the known costs of late-life reproduction in killer whales, can help explain the long postreproductive life spans of resident killer whales.
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http://dx.doi.org/10.1073/pnas.1903844116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936675PMC
December 2019

Advantages of Radiation Therapy Simulation with 0.35 Tesla Magnetic Resonance Imaging for Stereotactic Ablation of Spinal Metastases.

Pract Radiat Oncol 2020 Sep - Oct;10(5):339-344. Epub 2019 Nov 26.

Department of Radiation Oncology, Miller School of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida. Electronic address:

The hybrid 0.35T magnetic resonance imaging (MRI) and radiation therapy system functions in part as a simulation platform for treatment planning. We have found that the images generated are particularly helpful for planning of stereotactic radiation therapy for spinal metastases. Advantages include the following: (1) Low-field MRI mitigates magnetic susceptibility artifacts caused by spinal hardware. (2) Volumetric pulse sequence provides isotropic images for improved target delineation. (3) Wide-bore MRI in the radiation oncology department allows for easy simulation in treatment position for accurate fusion across imaging modalities. (4) When patients are treated on the MRI and radiation therapy hybrid device, adaptive radiation therapy is available for special situations to avoid mobile organs at risk.
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http://dx.doi.org/10.1016/j.prro.2019.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247919PMC
August 2021

B Cells and T Follicular Helper Cells Mediate Response to Checkpoint Inhibitors in High Mutation Burden Mouse Models of Breast Cancer.

Cell 2019 11;179(5):1191-1206.e21

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address:

This study identifies mechanisms mediating responses to immune checkpoint inhibitors using mouse models of triple-negative breast cancer. By creating new mammary tumor models, we find that tumor mutation burden and specific immune cells are associated with response. Further, we developed a rich resource of single-cell RNA-seq and bulk mRNA-seq data of immunotherapy-treated and non-treated tumors from sensitive and resistant murine models. Using this, we uncover that immune checkpoint therapy induces T follicular helper cell activation of B cells to facilitate the anti-tumor response in these models. We also show that B cell activation of T cells and the generation of antibody are key to immunotherapy response and propose a new biomarker for immune checkpoint therapy. In total, this work presents resources of new preclinical models of breast cancer with large mRNA-seq and single-cell RNA-seq datasets annotated for sensitivity to therapy and uncovers new components of response to immune checkpoint inhibitors.
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http://dx.doi.org/10.1016/j.cell.2019.10.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911685PMC
November 2019

Polygenic Risk Score Contribution to Psychosis Prediction in a Target Population of Persons at Clinical High Risk.

Am J Psychiatry 2020 02 12;177(2):155-163. Epub 2019 Nov 12.

Department of Psychiatry (Perkins, Barbee), Lineberger Bioinformatics Core (Ford), Renaissance Computing Institute (Jeffries), University of North Carolina, Chapel Hill; Center for Neurobehavioral Genetics (Olde Loohuis) and Departments of Psychiatry and Biobehavioral Sciences and Psychology (Bearden), University of California, Los Angeles; Hotchkiss Brain Institute, Department of Psychiatry, University of Calgary, Alberta, Canada (Addington); Department of Psychiatry (Cadenhead) and Center for Behavioral Genomics, Department of Psychiatry (Tsuang), University of California, San Diego; Department of Psychology, Yale University, New Haven, Conn. (Cannon); Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks, N.Y. (Cornblatt); Department of Psychiatry, University of California, San Francisco (Mathalon); Department of Psychiatry, Yale University, New Haven, Conn. (McGlashan, Woods); Department of Psychiatry, Harvard Medical School at Beth Israel Deaconess Medical Center and Massachusetts General Hospital, Boston (Seidman); and Departments of Psychology and Psychiatry, Emory University, Atlanta (Walker).

Objective: The 2-year risk of psychosis in persons who meet research criteria for a high-risk syndrome is about 15%-25%; improvements in risk prediction accuracy would benefit the development and implementation of preventive interventions. The authors sought to assess polygenic risk score (PRS) prediction of subsequent psychosis in persons at high risk and to determine the impact of adding the PRS to a previously validated psychosis risk calculator.

Methods: Persons meeting research criteria for psychosis high risk (N=764) and unaffected individuals (N=279) were followed for up to 2 years. The PRS was based on the latest schizophrenia and bipolar genome-wide association studies. Variables in the psychosis risk calculator included stressful life events, trauma, disordered thought content, verbal learning, information processing speed, and family history of psychosis.

Results: For Europeans, the PRS varied significantly by group and was higher in the psychosis converter group compared with both the nonconverter and unaffected groups, but was similar for the nonconverter group compared with the unaffected group. For non-Europeans, the PRS varied significantly by group; the difference between the converters and nonconverters was not significant, but the PRS was significantly higher in converters than in unaffected individuals, and it did not differ between nonconverters and unaffected individuals. The R (R adjusted for the rate of disease risk in the population being studied, here assuming a 2-year psychosis risk between 10% and 30%) for Europeans varied between 9.2% and 12.3% and for non-Europeans between 3.5% and 4.8%. The amount of risk prediction information contributed by the addition of the PRS to the risk calculator was less than severity of disordered thoughts and similar to or greater than for other variables. For Europeans, the PRS was correlated with risk calculator variables of information processing speed and verbal memory.

Conclusions: The PRS discriminates psychosis converters from nonconverters and modestly improves individualized psychosis risk prediction when added to a psychosis risk calculator. The schizophrenia PRS shows promise in enhancing risk prediction in persons at high risk for psychosis, although its potential utility is limited by poor performance in persons of non-European ancestry.
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http://dx.doi.org/10.1176/appi.ajp.2019.18060721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202227PMC
February 2020
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