Publications by authors named "Katherine Gallagher"

113 Publications

Seroprevalence of Antibodies to SARS-CoV-2 among Health Care Workers in Kenya.

Clin Infect Dis 2021 Apr 24. Epub 2021 Apr 24.

KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.

Background: Few studies have assessed the seroprevalence of antibodies against SARS-CoV-2 among Health Care Workers (HCWs) in Africa. We report findings from a survey among HCWs in three counties in Kenya.

Methods: We recruited 684 HCWs from Kilifi (rural), Busia (rural) and Nairobi (urban) counties. The serosurvey was conducted between 30th July 2020 and 4th December 2020. We tested for IgG antibodies to SARS-CoV-2 spike protein using ELISA. Assay sensitivity and specificity were 93% (95% CI 88-96%) and 99% (95% CI 98-99.5%), respectively. We adjusted prevalence estimates using Bayesian modeling to account for assay performance.

Results: Crude overall seroprevalence was 19.7% (135/684). After adjustment for assay performance seroprevalence was 20.8% (95% CrI 17.5-24.4%). Seroprevalence varied significantly (p<0.001) by site: 43.8% (CrI 35.8-52.2%) in Nairobi, 12.6% (CrI 8.8-17.1%) in Busia and 11.5% (CrI 7.2-17.6%) in Kilifi. In a multivariable model controlling for age, sex and site, professional cadre was not associated with differences in seroprevalence.

Conclusion: These initial data demonstrate a high seroprevalence of antibodies to SARS-CoV-2 among HCWs in Kenya. There was significant variation in seroprevalence by region, but not by cadre.
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http://dx.doi.org/10.1093/cid/ciab346DOI Listing
April 2021

Inhibition of macrophage histone demethylase JMJD3 protects against abdominal aortic aneurysms.

J Exp Med 2021 Jun;218(6)

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI.

Abdominal aortic aneurysms (AAAs) are a life-threatening disease for which there is a lack of effective therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is driven by macrophage infiltration, and the mechanisms regulating macrophage-mediated inflammation remain undefined. Recent evidence suggests that an epigenetic enzyme, JMJD3, plays a critical role in establishing macrophage phenotype. Using single-cell RNA sequencing of human AAA tissues, we identified increased JMJD3 in aortic monocyte/macrophages resulting in up-regulation of an inflammatory immune response. Mechanistically, we report that interferon-β regulates Jmjd3 expression via JAK/STAT and that JMJD3 induces NF-κB-mediated inflammatory gene transcription in infiltrating aortic macrophages. In vivo targeted inhibition of JMJD3 with myeloid-specific genetic depletion (JMJD3f/fLyz2Cre+) or pharmacological inhibition in the elastase or angiotensin II-induced AAA model preserved the repressive H3K27me3 on inflammatory gene promoters and markedly reduced AAA expansion and attenuated macrophage-mediated inflammation. Together, our findings suggest that cell-specific pharmacologic therapy targeting JMJD3 may be an effective intervention for AAA expansion.
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http://dx.doi.org/10.1084/jem.20201839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008365PMC
June 2021

Multidisciplinary Recommendations Regarding Post-Vaccine Adenopathy and Radiologic Imaging: Scientific Expert Panel.

Radiology 2021 Feb 24:210436. Epub 2021 Feb 24.

From Department of Radiology, Memorial Sloan Kettering Cancer Center, New York NY (A.S.B., R.P-J., M.E.H., K.N.F., K.M.G., A.T.L., R.Y., M.E.M., H.H., H.A.V.); Department of Radiology, Brigham and Women's Hospital, Boston MA (S.A.C., A.B.S.); Department of Imaging, Dana-Farber Cancer Institute, Boston MA (S.A.C., A.B.S.); Division of Diagnostic Imaging, MD Anderson Cancer Center, Houston TX (M.M.C., M.H.); Department of Head and Neck Surgery, MD Anderson Cancer Center, Houston TX (E.Y.H.); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston MA (E.L.M.).

Vaccination-associated adenopathy is a frequent imaging finding after administration of COVID-19 vaccines that may lead to a diagnostic conundrum in patients with manifest or suspected cancer, in whom it may be indistinguishable from malignant nodal involvement. To help the medical community address this concern in the absence of studies and evidence-based guidelines, this paper offers recommendations developed by a multidisciplinary panel of experts from three of the leading tertiary care cancer centers in the United States. According to these recommendations, some routine imaging examinations, such as those for screening, should be scheduled before or at least 6 weeks after the final vaccination dose to allow for any reactive adenopathy to resolve. However, there should be no delay of other clinically indicated imaging (e.g., for acute symptoms, short-interval treatment monitoring, urgent treatment planning or complications) due to prior vaccination. The vaccine should be administered on the side contralateral to the primary or suspected cancer, and both doses should be administered in the same arm. Vaccination information (date(s) administered, injection site(s), laterality, and type of vaccine) should be included in every pre-imaging patient questionnaire, and this information should be made readily available to interpreting radiologists. Clear and effective communication between patients, radiologists, referring physician teams and the general public should be considered of the highest priority when managing adenopathy in the setting of COVID-19 vaccination. Summary COVID-19-vaccination-related adenopathy is a frequent imaging finding that may lead to a diagnostic conundrum in patients with manifest or suspected cancer, in whom it may be indistinguishable from malignant nodal involvement. This special report offers recommendations developed by a multidisciplinary panel of experts from three of the leading tertiary care cancer centers in the United States.
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http://dx.doi.org/10.1148/radiol.2021210436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909071PMC
February 2021

Vaccine strategies to reduce the burden of pneumococcal disease in HIV-infected adults in Africa.

Expert Rev Vaccines 2020 11 3;19(11):1085-1092. Epub 2020 Dec 3.

Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine , London, UK.

Introduction: is the leading cause of invasive bacterial disease, globally. Despite antiretroviral therapy, adults infected with human immunodeficiency virus (HIV) are also at high risk of pneumococcal carriage and disease. Pneumococcal conjugate vaccines (PCVs) provide effective protection against vaccine serotype (VT) carriage and disease in children, and have been introduced worldwide, including most HIV-affected low- and middle-income countries. Unlike high-income countries, the circulation of VT persists in the PCV era in some low-income countries and results in a continued high burden of pneumococcal disease in HIV-infected adults. Moreover, no routine vaccination that directly protects HIV-infected adults in such settings has been implemented.

Areas Covered: Nonsystematic review on the pneumococcal burden in HIV-infected adults and vaccine strategies to reduce this burden.

Expert Opinion: We propose and discuss the relative merit of changing the infant PCV program to use (1a) a two prime plus booster dose schedule, (1b) a two prime plus booster dose schedule with an additional booster dose at school entry, to directly vaccinate (2a) HIV-infected adults or vaccinating (2b) HIV-infected pregnant women for direct protection, with added indirect protection to the high-risk neonates. We identify key knowledge gaps for such an evaluation and propose strategies to overcome them.
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http://dx.doi.org/10.1080/14760584.2020.1843435DOI Listing
November 2020

Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Kenyan blood donors.

Science 2021 01 11;371(6524):79-82. Epub 2020 Nov 11.

KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Africa is poorly described. The first case of SARS-CoV-2 in Kenya was reported on 12 March 2020, and an overwhelming number of cases and deaths were expected, but by 31 July 2020, there were only 20,636 cases and 341 deaths. However, the extent of SARS-CoV-2 exposure in the community remains unknown. We determined the prevalence of anti-SARS-CoV-2 immunoglobulin G among blood donors in Kenya in April-June 2020. Crude seroprevalence was 5.6% (174 of 3098). Population-weighted, test-performance-adjusted national seroprevalence was 4.3% (95% confidence interval, 2.9 to 5.8%) and was highest in urban counties Mombasa (8.0%), Nairobi (7.3%), and Kisumu (5.5%). SARS-CoV-2 exposure is more extensive than indicated by case-based surveillance, and these results will help guide the pandemic response in Kenya and across Africa.
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http://dx.doi.org/10.1126/science.abe1916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877494PMC
January 2021

Defining features of diabetes resilience in emerging adults with type 1 diabetes.

Pediatr Diabetes 2021 Mar 18;22(2):345-353. Epub 2020 Oct 18.

Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.

Background: Emerging adulthood presents unique challenges for type 1 diabetes (T1D) management. Barriers to achieving optimal diabetes outcomes have been studied but less is known about how emerging adults overcome these challenges. Characterizing emerging adults' protective factors may help guide T1D care during this developmental period. We anticipated identifying social, cognitive, and behavioral protective factors and were open to additional themes.

Methods: We analyzed transcripts from semi-structured qualitative interviews with 62 emerging adults (age 18-24 years) with T1D using hybrid thematic analysis. Interviews queried about participants' perspectives on diabetes management challenges, how they overcome challenges, and diabetes resilience.

Results: We categorized responses into three types of protective factors: (a) Social: Interpersonal strategies such as obtaining tangible support (especially from parents) and emotional support from friends, medical professionals, and community leaders. (b) Cognitive: Believing one can live a "normal" life with T1D, benefit-finding, and viewing diabetes management as an important part of life. (c) Behavioral: Proactively planning for diabetes challenges, maintaining a consistent routine while allowing for flexibility, balancing diabetes and non-diabetes activities, and using diabetes-specific and general technologies to support self-management.

Conclusions: The adaptive approaches emerging adults with T1D use to handle the challenges of diabetes include seeking interpersonal support, managing their thoughts about T1D, and taking specific actions to prevent or resolve challenges. Helping emerging adults identify and strengthen their protective factors has potential to affect clinical outcomes. Strengths-based assessment and clinical attention to protective factors may prepare adolescents to successfully manage the challenges of transition to adult care.
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http://dx.doi.org/10.1111/pedi.13136DOI Listing
March 2021

Surveillance of endemic human coronaviruses (HCoV-NL63, OC43 and 229E) associated with childhood pneumonia in Kilifi, Kenya.

Wellcome Open Res 2020 22;5:150. Epub 2020 Sep 22.

Epidemiology and Demography Department, Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya.

Human coronaviruses (HCoVs) circulate endemically in human populations, often with seasonal variation. We describe the long-term patterns of paediatric disease associated with three of these viruses, HCoV-NL63, OC43 and 229E, in coastal Kenya. Continuous surveillance of pneumonia admissions was conducted at the Kilifi county hospital (KCH) located in the northern coastal region of Kenya. Children aged <5 years admitted to KCH with clinically defined syndromic severe or very severe pneumonia were recruited. Respiratory samples were taken and tested for 15 virus targets, using real-time polymerase chain reaction. Unadjusted odds ratios were used to estimate the association between demographic and clinical characteristics and HCoV positivity. From 2007 to 2019, we observed 11,445 pneumonia admissions, of which 314 (3.9%) tested positive for at least one of the HCoV types surveyed in the study. There were 129 (41.1%) OC43, 99 (31.5%) 229E, 74 (23.6%) NL63 positive cases and 12 (3.8%) cases of HCoV to HCoV coinfection.  Among HCoV positive cases, 47% (n=147) were coinfected with other respiratory virus pathogens. The majority of HCoV cases were among children aged <1 year (66%, n=208), though there was was no change in the proportion infected by age. HCoV-OC43 was predominant of the three HCoV types throughout the surveillance period. Evidence for seasonality was not identified. Overall, 4% of paediatric pneumonia admissions were associated with three endemic HCoVs, with a high proportion of cases co-occurring with another respiratory virus, no clear seasonal pattern, and with the age-distribution of cases following that of pneumonia admissions (i.e. highest in infants). These observations suggest, at most, a small severe disease contribution of endemic HCoVs in this tropical setting and offer insight into their potential future burden and epidemiological characteristics.
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http://dx.doi.org/10.12688/wellcomeopenres.16037.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7512035PMC
September 2020

Epigenetic regulation of the PGE2 pathway modulates macrophage phenotype in normal and pathologic wound repair.

JCI Insight 2020 09 3;5(17). Epub 2020 Sep 3.

Section of Vascular Surgery, Department of Surgery.

Macrophages are a primary immune cell involved in inflammation, and their cell plasticity allows for transition from an inflammatory to a reparative phenotype and is critical for normal tissue repair following injury. Evidence suggests that epigenetic alterations play a critical role in establishing macrophage phenotype and function during normal and pathologic wound repair. Here, we find in human and murine wound macrophages that cyclooxygenase 2/prostaglandin E2 (COX-2/PGE2) is elevated in diabetes and regulates downstream macrophage-mediated inflammation and host defense. Using single-cell RNA sequencing of human wound tissue, we identify increased NF-κB-mediated inflammation in diabetic wounds and show increased COX-2/PGE2 in diabetic macrophages. Further, we identify that COX-2/PGE2 production in wound macrophages requires epigenetic regulation of 2 key enzymes in the cytosolic phospholipase A2/COX-2/PGE2 (cPLA2/COX-2/PGE2) pathway. We demonstrate that TGF-β-induced miRNA29b increases COX-2/PGE2 production via inhibition of DNA methyltransferase 3b-mediated hypermethylation of the Cox-2 promoter. Further, we find mixed-lineage leukemia 1 (MLL1) upregulates cPLA2 expression and drives COX-2/PGE2. Inhibition of the COX-2/PGE2 pathway genetically (Cox2fl/fl Lyz2Cre+) or with a macrophage-specific nanotherapy targeting COX-2 in tissue macrophages reverses the inflammatory macrophage phenotype and improves diabetic tissue repair. Our results indicate the epigenetically regulated PGE2 pathway controls wound macrophage function, and cell-targeted manipulation of this pathway is feasible to improve diabetic wound repair.
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http://dx.doi.org/10.1172/jci.insight.138443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526451PMC
September 2020

Palmitate-TLR4 signaling regulates the histone demethylase, JMJD3, in macrophages and impairs diabetic wound healing.

Eur J Immunol 2020 12 20;50(12):1929-1940. Epub 2020 Jul 20.

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.

Chronic macrophage inflammation is a hallmark of type 2 diabetes (T2D) and linked to the development of secondary diabetic complications. T2D is characterized by excess concentrations of saturated fatty acids (SFA) that activate innate immune inflammatory responses, however, mechanism(s) by which SFAs control inflammation is unknown. Using monocyte-macrophages isolated from human blood and murine models, we demonstrate that palmitate (C16:0), the most abundant circulating SFA in T2D, increases expression of the histone demethylase, Jmjd3. Upregulation of Jmjd3 results in removal of the repressive histone methylation (H3K27me3) mark on NFκB-mediated inflammatory gene promoters driving macrophage-mediated inflammation. We identify that the effects of palmitate are fatty acid specific, as laurate (C12:0) does not regulate Jmjd3 and the associated inflammatory profile. Further, palmitate-induced Jmjd3 expression is controlled via TLR4/MyD88-dependent signaling mechanism, where genetic depletion of TLR4 (Tlr4 ) or MyD88 (MyD88 ) negated the palmitate-induced changes in Jmjd3 and downstream NFκB-induced inflammation. Pharmacological inhibition of Jmjd3 using a small molecule inhibitor (GSK-J4) reduced macrophage inflammation and improved diabetic wound healing. Together, we conclude that palmitate contributes to the chronic Jmjd3-mediated activation of macrophages in diabetic peripheral tissue and a histone demethylase inhibitor-based therapy may represent a novel treatment for nonhealing diabetic wounds.
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http://dx.doi.org/10.1002/eji.202048651DOI Listing
December 2020

Ultrafast dynamic contrast-enhanced breast MRI may generate prognostic imaging markers of breast cancer.

Breast Cancer Res 2020 05 28;22(1):58. Epub 2020 May 28.

Breast Imaging Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Ultrafast dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)-derived kinetic parameters have demonstrated at least equivalent accuracy to standard DCE-MRI in differentiating malignant from benign breast lesions. However, it is unclear if they have any efficacy as prognostic imaging markers. The aim of this study was to investigate the relationship between ultrafast DCE-MRI-derived kinetic parameters and breast cancer characteristics.

Methods: Consecutive breast MRI examinations between February 2017 and January 2018 were retrospectively reviewed to determine those examinations that meet the following inclusion criteria: (1) BI-RADS 4-6 MRI performed on a 3T scanner with a 16-channel breast coil and (2) a hybrid clinical protocol with 15 phases of ultrafast DCE-MRI (temporal resolution of 2.7-4.6 s) followed by early and delayed phases of standard DCE-MRI. The study included 125 examinations with 142 biopsy-proven breast cancer lesions. Ultrafast DCE-MRI-derived kinetic parameters (maximum slope [MS] and bolus arrival time [BAT]) were calculated for the entire volume of each lesion. Comparisons of these parameters between different cancer characteristics were made using generalized estimating equations, accounting for the presence of multiple lesions per patient. All comparisons were exploratory and adjustment for multiple comparisons was not performed; P values < 0.05 were considered statistically significant.

Results: Significantly larger MS and shorter BAT were observed for invasive carcinoma than ductal carcinoma in situ (DCIS) (P < 0.001 and P = 0.008, respectively). Significantly shorter BAT was observed for invasive carcinomas with more aggressive characteristics than those with less aggressive characteristics: grade 3 vs. grades 1-2 (P = 0.025), invasive ductal carcinoma vs. invasive lobular carcinoma (P = 0.002), and triple negative or HER2 type vs. luminal type (P < 0.001).

Conclusions: Ultrafast DCE-MRI-derived parameters showed a strong relationship with some breast cancer characteristics, especially histopathology and molecular subtype.
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http://dx.doi.org/10.1186/s13058-020-01292-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254650PMC
May 2020

Bleeding and thrombotic outcomes associated with postoperative use of direct oral anticoagulants after open peripheral artery bypass procedures.

J Vasc Surg 2020 12 8;72(6):1996-2005.e4. Epub 2020 Apr 8.

Section of Vascular Surgery, Department of Surgery, University of Michigan Health System, Ann Arbor, Mich. Electronic address:

Objective: Widespread adoption of direct oral anticoagulants (DOACs) for atrial fibrillation and venous thromboembolism treatment has resulted in peripheral bypass patients receiving therapeutic anticoagulation with DOACs postoperatively. This study was undertaken to evaluate patient outcomes after open peripheral bypass based on anticoagulation treatment.

Methods: Postoperative treatment and outcomes of patients undergoing peripheral bypass operations between January 2012 and December 2017 from a statewide multicenter quality improvement registry were examined. Surgeons participating in the registry were surveyed on practice patterns regarding DOACs in bypass patients. Multivariate logistic regression was performed for 30-day transfusion outcomes, and multiple linear regression was performed for length of stay.

Results: Among 9682 patients, 7685 patients received no anticoagulation, whereas 1379 received a vitamin K antagonist (VKA) and 618 received a DOAC postoperatively. Patients receiving anticoagulation compared with no anticoagulation had a higher body mass index and were more likely to have preoperative anemia, congestive heart failure, and atrial fibrillation (all P < .001). Compared with patients receiving VKAs, patients receiving DOACs were less likely to have chronic kidney disease (P = .002) and more likely to have atrial fibrillation (P < .001). The shortest length of stay was among patients receiving no anticoagulation (median, 5 days; interquartile range, 3-9 days; P < .001), followed by DOACs (median, 6 days; interquartile range 3-11 days; P < .001) and VKAs (median, 8 days; interquartile range, 5-13 days; P < .001). Compared with patients receiving VKAs postoperatively, there was no difference in readmission for anticoagulation complications, bypass thrombectomy or thrombolysis, major amputation, or graft patency at 1 year among patients receiving DOACs. On multivariate logistic regression, patients receiving a DOAC (odds ratio, 0.743; confidence interval, 0.59-0.94; P = .011) or no anticoagulation (odds ratio, 0.792; confidence interval, 0.69-0.91; P = .001) were less likely to require transfusion within 30 days than patients taking VKAs. Approximately 70% of the surveyed surgeons reported that they "sometimes" or "always" use DOACs instead of VKAs for protection of a high-risk bypass.

Conclusions: Among patients undergoing lower extremity surgical bypass, those receiving a DOAC postoperatively had a shorter length of stay and were less likely to receive a transfusion in 30 days without compromising graft patency and readmission for anticoagulation complications, thrombectomy, or thrombolysis or affecting amputation rate compared with those receiving a VKA. A majority of surgeons within the quality collaborative have adopted the use of DOACs after peripheral bypass, suggesting the need for a prospective trial evaluating DOAC safety and efficacy in patients requiring anticoagulation for high-risk bypass grafts.
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http://dx.doi.org/10.1016/j.jvs.2020.02.021DOI Listing
December 2020

Epigenetic Regulation of TLR4 in Diabetic Macrophages Modulates Immunometabolism and Wound Repair.

J Immunol 2020 05 23;204(9):2503-2513. Epub 2020 Mar 23.

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI 48109;

Macrophages are critical for the initiation and resolution of the inflammatory phase of wound healing. In diabetes, macrophages display a prolonged inflammatory phenotype preventing tissue repair. TLRs, particularly TLR4, have been shown to regulate myeloid-mediated inflammation in wounds. We examined macrophages isolated from wounds of patients afflicted with diabetes and healthy controls as well as a murine diabetic model demonstrating dynamic expression of TLR4 results in altered metabolic pathways in diabetic macrophages. Further, using a myeloid-specific mixed-lineage leukemia 1 (MLL1) knockout ( ), we determined that MLL1 drives expression in diabetic macrophages by regulating levels of histone H3 lysine 4 trimethylation on the promoter. Mechanistically, MLL1-mediated epigenetic alterations influence diabetic macrophage responsiveness to TLR4 stimulation and inhibit tissue repair. Pharmacological inhibition of the TLR4 pathway using a small molecule inhibitor (TAK-242) as well as genetic depletion of either ( ) or myeloid-specific resulted in improved diabetic wound healing. These results define an important role for MLL1-mediated epigenetic regulation of TLR4 in pathologic diabetic wound repair and suggest a target for therapeutic manipulation.
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http://dx.doi.org/10.4049/jimmunol.1901263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443363PMC
May 2020

TNF-α regulates diabetic macrophage function through the histone acetyltransferase MOF.

JCI Insight 2020 03 12;5(5). Epub 2020 Mar 12.

Department of Surgery.

A critical component of wound healing is the transition from the inflammatory phase to the proliferation phase to initiate healing and remodeling of the wound. Macrophages are critical for the initiation and resolution of the inflammatory phase during wound repair. In diabetes, macrophages display a sustained inflammatory phenotype in late wound healing characterized by elevated production of inflammatory cytokines, such as TNF-α. Previous studies have shown that an altered epigenetic program directs diabetic macrophages toward a proinflammatory phenotype, contributing to a sustained inflammatory phase. Males absent on the first (MOF) is a histone acetyltransferase (HAT) that has been shown be a coactivator of TNF-α signaling and promote NF-κB-mediated gene transcription in prostate cancer cell lines. Based on MOF's role in TNF-α/NF-κB-mediated gene expression, we hypothesized that MOF influences macrophage-mediated inflammation during wound repair. We used myeloid-specific Mof-knockout (Lyz2Cre Moffl/fl) and diet-induced obese (DIO) mice to determine the function of MOF in diabetic wound healing. MOF-deficient mice exhibited reduced inflammatory cytokine gene expression. Furthermore, we found that wound macrophages from DIO mice had elevated MOF levels and higher levels of acetylated histone H4K16, MOF's primary substrate of HAT activity, on the promoters of inflammatory genes. We further identified that MOF expression could be stimulated by TNF-α and that treatment with etanercept, an FDA-approved TNF-α inhibitor, reduced MOF levels and improved wound healing in DIO mice. This report is the first to our knowledge to define an important role for MOF in regulating macrophage-mediated inflammation in wound repair and identifies TNF-α inhibition as a potential therapy for the treatment of chronic inflammation in diabetic wounds.
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http://dx.doi.org/10.1172/jci.insight.132306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141388PMC
March 2020

Regulation of heterotopic ossification by monocytes in a mouse model of aberrant wound healing.

Nat Commun 2020 02 5;11(1):722. Epub 2020 Feb 5.

Section of Plastic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, 48109, USA.

Heterotopic ossification (HO) is an aberrant regenerative process with ectopic bone induction in response to musculoskeletal trauma, in which mesenchymal stem cells (MSC) differentiate into osteochondrogenic cells instead of myocytes or tenocytes. Despite frequent cases of hospitalized musculoskeletal trauma, the inflammatory responses and cell population dynamics that regulate subsequent wound healing and tissue regeneration are still unclear. Here we examine, using a mouse model of trauma-induced HO, the local microenvironment of the initial post-injury inflammatory response. Single cell transcriptome analyses identify distinct monocyte/macrophage populations at the injury site, with their dynamic changes over time elucidated using trajectory analyses. Mechanistically, transforming growth factor beta-1 (TGFβ1)-producing monocytes/macrophages are associated with HO and aberrant chondrogenic progenitor cell differentiation, while CD47-activating peptides that reduce systemic macrophage TGFβ levels and help ameliorate HO. Our data thus implicate CD47 activation as a therapeutic approach for modulating monocyte/macrophage phenotypes, MSC differentiation and HO formation during wound healing.
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http://dx.doi.org/10.1038/s41467-019-14172-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002453PMC
February 2020

Ly6CLo Monocyte/Macrophages are Essential for Thrombus Resolution in a Murine Model of Venous Thrombosis.

Thromb Haemost 2020 Feb 30;120(2):289-299. Epub 2019 Dec 30.

Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States.

Venous thrombosis (VT) resolution is a complex process, resembling sterile wound healing. Infiltrating blood-derived monocyte/macrophages (Mo/MΦs) are essential for the regulation of inflammation in tissue repair. These cells differentiate into inflammatory (CD11bLy6C) or proreparative (CD11bLy6C) subtypes. Previous studies have shown that infiltrating Mo/MΦs are important for VT resolution, but the precise roles of different Mo/MΦs subsets are not well understood. Utilizing murine models of stasis and stenosis inferior vena cava thrombosis in concert with a Mo/MΦ depletion model (CD11b-diphtheria toxin receptor [DTR]-expressing mice), we examined the effect of Mo/MΦ depletion on thrombogenesis and VT resolution. In the setting of an 80 to 90% reduction in circulating CD11bMo/MΦs, we demonstrated that Mo/MΦs are not essential for thrombogenesis, with no difference in thrombus size, neutrophil recruitment, or neutrophil extracellular traps found. Conversely, CD11bMo/MΦ are essential for VT resolution. Diphtheria toxoid (DTx)-mediated depletion after thrombus creation depleted primarily CD11bLy6C Mo/MΦs and resulted in larger thrombi. DTx-mediated depletion did not alter CD11bLy6C Mo/MΦ recruitment, suggesting a protective effect of CD11bLy6C Mo/MΦs in VT resolution. Confirmatory Mo/MΦ depletion with clodronate lysosomes showed a similar phenotype, with failure to resolve VT. Adoptive transfer of CD11bLy6C Mo/MΦs into Mo/MΦ-depleted mice reversed the phenotype, restoring normal thrombus resolution. These findings suggest that CD11bLy6C Mo/MΦs are essential for normal VT resolution, consistent with the known proreparative function of this subset, and that further study of Mo/MΦ subsets may identify targets for immunomodulation to accelerate and improve thrombosis resolution.
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http://dx.doi.org/10.1055/s-0039-3400959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365023PMC
February 2020

Efficacy and immunogenicity of a single dose of human papillomavirus vaccine compared to no vaccination or standard three and two-dose vaccination regimens: A systematic review of evidence from clinical trials.

Vaccine 2020 02 20;38(6):1302-1314. Epub 2019 Dec 20.

Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom; Mwanza Intervention Trials Unit, National Institute of Medical Research, Mwanza, Tanzania.

Objectives: This study aimed to systematically review the literature on the efficacy and immunogenicity of single-dose HPV vaccination compared to no vaccination or multi-dose schedules among vaccine trial participants.

Methods: Medline, EMBASE, Global Health Database and Cochrane Central Register of Controlled Trials were searched for publications and conference abstracts (dated January 1999-August 2018) using MeSH and non-MeSH terms for human papillomavirus AND vaccines AND (immunogenicity OR efficacy/effectiveness) AND dosage. Search results were screened against pre-specified eligibility criteria. Data were extracted from included articles, and a narrative synthesis conducted on efficacy against HPV16/18 infection and humoral immunogenicity.

Results: Seven of 6,523 unique records identified were included in the review. Six were nested observational studies of participants randomised to receive two or three doses in three large HPV vaccine trials, in which some participants did not complete their allocated schedules. One small pilot study prospectively allocated participants to receive one or no vaccine dose. Frequency of HPV16/18 infection was low (e.g. <1% for 12-month-persistent infection) in all vaccinated participants up to seven years post vaccination and did not significantly differ by number of doses (p > 0.05 in all cases). Frequency of infection was significantly lower in one-dose recipients compared to unvaccinated controls (p < 0.01 for all infection endpoints in each study). HPV16/18 seropositivity rates were high in all HPV vaccine recipients (100% in three of four studies reporting this endpoint), though antibody levels were lower with one compared to two or three doses.

Conclusions: This review supports the premise that one HPV vaccine dose may be as effective in preventing HPV infection as multi-dose schedules in healthy young women. However, it also highlights the paucity of available evidence from purpose-designed, prospectively-randomised trials. Results from ongoing clinical trials assessing the efficacy and immunogenicity of single-dose HPV vaccination compared to currently-recommended schedules are awaited.
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http://dx.doi.org/10.1016/j.vaccine.2019.12.017DOI Listing
February 2020

Accessing the academic influence of vascular surgeons within the National Institutes of Health iCite database.

J Vasc Surg 2020 05 9;71(5):1741-1748.e2. Epub 2019 Dec 9.

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, Mich. Electronic address:

Objective: A diverse array of measures are used to evaluate academic physicians. One critical factor is the scholarly influence an author has on the research discourse within a field. The National Institutes of Health recently developed the Relative Citation Ratio (RCR) as a method to quantify the influence of published research. The aim of this study was to examine the academic influence of vascular surgeons using RCR within common vascular disease research fields.

Methods: Using the PubMed and National Institutes of Health iCite databases, scientific fields of abdominal and thoracic aortic aneurysm, peripheral artery disease (PAD), cerebral vascular occlusive disease, deep venous thrombosis (DVT), and venous insufficiency were queried for the highest rated RCR articles in each category (2007-2012). To calculate the RCR, article citation rates are divided by an expected citation rate derived from performance of articles in the same field, with the resulting RCR being level and field independent. Article categories were divided into basic science, health services, and clinical research on the basis of two independent reviews. For articles, academic backgrounds of the first, second, and last authors ("influential authors") were collected analyzing procedural specialty: surgery, medicine subspecialty (cardiology, neurology, nephrology), radiology/engineering, and other (anesthesia and pediatrics). Statistical significance between scientific fields and academic background was determined using Student t-test or analysis of variance followed by Newman-Keuls post hoc test.

Results: The academic influence of vascular surgeons varied substantially by the scientific field. Vascular surgeons compared with medical specialists were found to have the highest academic influence in abdominal aortic aneurysm research, composing 51% of the influential authors on the highest rated RCR studies (5.9 ± 0.8 vs 5.6 ± 0.8; P = .6). In contrast, vascular surgeons composed only 13% of influential authors compared with medical specialists in DVT (RCR, 2.6 ± 0.3 vs 15.7 ± 1.7; P < .003) and 18% in PAD (RCR, 1.9 ± 0.5 vs 2.1 ± 0.2; P = .78) research fields. Grouping all vascular fields of study together, no difference in RCR was found between vascular surgery and radiology/engineering. However, the mean RCR was significantly lower for vascular surgeons compared with medical subspecialties (4.5 ± 0.4 vs 6.8 ± 0.5; P < .05).

Conclusions: Vascular surgeons exhibit a moderate academic influence in the field of aneurysmal disease but lag behind medical subspecialists in high-impact scientific contributions to the fields of PAD and DVT. Innovative strategies and collaborations are likely needed to increase the influence of vascular surgeons on the academic discourse of several vascular disease research fields.
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http://dx.doi.org/10.1016/j.jvs.2019.09.036DOI Listing
May 2020

Sepsis Induces Prolonged Epigenetic Modifications in Bone Marrow and Peripheral Macrophages Impairing Inflammation and Wound Healing.

Arterioscler Thromb Vasc Biol 2019 11 5;39(11):2353-2366. Epub 2019 Sep 5.

From the Section of Vascular Surgery, Department of Surgery (F.M.D., A.D., A.D.J., A.S.K., A.T.O., W.J.M., K.A.G.), University of Michigan, Ann Arbor.

Objective: Sepsis represents an acute life-threatening disorder resulting from a dysregulated host response. For patients who survive sepsis, there remains long-term consequences, including impaired inflammation, as a result of profound immunosuppression. The mechanisms involved in this long-lasting deficient immune response are poorly defined. Approach and Results: Sepsis was induced using the murine model of cecal ligation and puncture. Following a full recovery period from sepsis physiology, mice were subjected to our wound healing model and wound macrophages (CD11b+, CD3-, CD19-, Ly6G-) were sorted. Post-sepsis mice demonstrated impaired wound healing and decreased reepithelization in comparison to controls. Further, post-sepsis bone marrow-derived macrophages and wound macrophages exhibited decreased expression of inflammatory cytokines vital for wound repair (IL [interleukin]-1β, IL-12, and IL-23). To evaluate if decreased inflammatory gene expression was secondary to epigenetic modification, we conducted chromatin immunoprecipitation on post-sepsis bone marrow-derived macrophages and wound macrophages. This demonstrated decreased expression of , an epigenetic enzyme, and impaired histone 3 lysine 4 trimethylation (activation mark) at NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells)-binding sites on inflammatory gene promoters in bone marrow-derived macrophages and wound macrophages from postcecal ligation and puncture mice. Bone marrow transplantation studies demonstrated epigenetic modifications initiate in bone marrow progenitor/stem cells following sepsis resulting in lasting impairment in peripheral macrophage function. Importantly, human peripheral blood leukocytes from post-septic patients demonstrate a significant reduction in compared with nonseptic controls.

Conclusions: These data demonstrate that severe sepsis induces stable mixed-lineage leukemia 1-mediated epigenetic modifications in the bone marrow, which are passed to peripheral macrophages resulting in impaired macrophage function and deficient wound healing persisting long after sepsis recovery.
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http://dx.doi.org/10.1161/ATVBAHA.119.312754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818743PMC
November 2019

Differentiation between subcentimeter carcinomas and benign lesions using kinetic parameters derived from ultrafast dynamic contrast-enhanced breast MRI.

Eur Radiol 2020 Feb 29;30(2):756-766. Epub 2019 Aug 29.

Breast Imaging Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Objectives: This study aims to evaluate ultrafast DCE-MRI-derived kinetic parameters that reflect contrast agent inflow effects in differentiating between subcentimeter BI-RADS 4-5 breast carcinomas and benign lesions.

Methods: We retrospectively reviewed consecutive 3-T MRI performed from February to October 2017, during which ultrafast DCE-MRI was performed as part of a hybrid clinical protocol with conventional DCE-MRI. In total, 301 female patients with 369 biopsy-proven breast lesions were included. Ultrafast DCE-MRI was acquired continuously over approximately 60 s (temporal resolution, 2.7-7.1 s/phase) starting simultaneously with the start of contrast injection. Four ultrafast DCE-MRI-derived kinetic parameters (maximum slope [MS], contrast enhancement ratio [CER], bolus arrival time [BAT], and initial area under gadolinium contrast agent concentration [IAUGC]) and one conventional DCE-MRI-derived kinetic parameter (signal enhancement ratio [SER]) were calculated for each lesion. Wilcoxon rank sum test or Fisher's exact test was performed to compare kinetic parameters, volume, diameter, age, and BI-RADS morphological descriptors between subcentimeter carcinomas and benign lesions. Univariate/multivariate logistic regression analyses were performed to determine predictive parameters for subcentimeter carcinomas.

Results: In total, 125 lesions (26 carcinomas and 99 benign lesions) were identified as BI-RADS 4-5 subcentimeter lesions. Subcentimeter carcinomas demonstrated significantly larger MS and SER and shorter BAT than benign lesions (p = 0.0117, 0.0046, and 0.0102, respectively). MS, BAT, and age were determined as significantly predictive for subcentimeter carcinoma (p = 0.0208, 0.0023, and < 0.0001, respectively).

Conclusions: Ultrafast DCE-MRI-derived kinetic parameters may be useful in differentiating subcentimeter BI-RADS 4 and 5 carcinomas from benign lesions.

Key Points: • Ultrafast DCE-MRI can generate kinetic parameters, effectively differentiating breast carcinomas from benign lesions. • Subcentimeter carcinomas demonstrated significantly larger maximum slope and shorter bolus arrival time than benign lesions. • Maximum slope and bolus arrival time contribute to better management of suspicious subcentimeter breast lesions.
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http://dx.doi.org/10.1007/s00330-019-06392-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570436PMC
February 2020

The Histone Methyltransferase Setdb2 Modulates Macrophage Phenotype and Uric Acid Production in Diabetic Wound Repair.

Immunity 2019 08 23;51(2):258-271.e5. Epub 2019 Jul 23.

Department of Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Macrophage plasticity is critical for normal tissue repair to ensure transition from the inflammatory to the proliferative phase of healing. We examined macrophages isolated from wounds of patients afflicted with diabetes and of healthy controls and found differential expression of the methyltransferase Setdb2. Myeloid-specific deletion of Setdb2 impaired the transition of macrophages from an inflammatory phenotype to a reparative one in normal wound healing. Mechanistically, Setdb2 trimethylated histone 3 at NF-κB binding sites on inflammatory cytokine gene promoters to suppress transcription. Setdb2 expression in wound macrophages was regulated by interferon (IFN) β, and under diabetic conditions, this IFNβ-Setdb2 axis was impaired, leading to a persistent inflammatory macrophage phenotype in diabetic wounds. Setdb2 regulated the expression of xanthine oxidase and thereby the uric acid (UA) pathway of purine catabolism in macrophages, and pharmacologic targeting of Setdb2 or the UA pathway improved healing. Thus, Setdb2 regulates macrophage plasticity during normal and pathologic wound repair and is a target for therapeutic manipulation.
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http://dx.doi.org/10.1016/j.immuni.2019.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703945PMC
August 2019

Invited commentary.

J Vasc Surg 2019 08;70(2):598-599

Ann Arbor, Mich.

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http://dx.doi.org/10.1016/j.jvs.2018.10.010DOI Listing
August 2019

SIRT3 Regulates Macrophage-Mediated Inflammation in Diabetic Wound Repair.

J Invest Dermatol 2019 12 15;139(12):2528-2537.e2. Epub 2019 Jun 15.

Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA. Electronic address:

Control of inflammation is critical for the treatment of nonhealing wounds, but a delicate balance exists between early inflammation that is essential for normal tissue repair and the pathologic inflammation that can occur later in the repair process. This necessitates the development of novel therapies that can target inflammation at the appropriate time during repair. Here, we found that SIRT3 is essential for normal healing and regulates inflammation in wound macrophages after injury. Under prediabetic conditions, SIRT3 was decreased in wound macrophages and resulted in dysregulated inflammation. In addition, we found that FABP4 regulates SIRT3 in human blood monocytes, and inhibition of FABP4 in wound macrophages decreases inflammatory cytokine expression, making FABP4 a viable target for the regulation of excess inflammation and wound repair in diabetes. Using a series of ex vivo and in vivo studies with genetically engineered mouse models and diabetic human monocytes, we showed that FABP4 expression is epigenetically upregulated in diabetic wound macrophages and, in turn, diminishes SIRT3 expression, thereby promoting inflammation. These findings have significant implications for controlling inflammation and promoting tissue repair in diabetic wounds.
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http://dx.doi.org/10.1016/j.jid.2019.05.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185380PMC
December 2019

Variation in Hospital Door-to-Intervention Time for Ruptured AAAs and Its Association with Outcomes.

Ann Vasc Surg 2020 Jan 13;62:83-91. Epub 2019 Jun 13.

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI. Electronic address:

Background: A ruptured abdominal aortic aneurysm (rAAA) is a life-threatening condition that carries a high mortality rate. Recent guidelines have recommended a goal "door-to-intervention" time of ≤90 minutes despite a paucity of evidence to support this goal. The aim of this study was to analyze recent trends in door-to-intervention time for rAAAs and determine the effect of the 90-minute door-to-intervention benchmark on postoperative complications.

Methods: A retrospective analysis of all patients who underwent open aortic repair (OAR) or endovascular aneurysm repair (EVAR) of a rAAA in the Vascular Quality Initiative database (2003-2018) was performed. Variation in door-to-intervention time was analyzed at the patient and hospital level. Patients were dichotomized into ≤90 or >90 minute door-to-intervention time cohorts. Hierarchical modeling controlling for the hospital random effect and multivariate logistic models was used to analyze the association on 30-day mortality and major in-hospital complications.

Results: A total of 3,630 operative cases for rAAA were identified (1696 OAR and 1934 EVAR). For the OAR cohort, 1035 patients (61%) had a door-to-intervention time of ≤90 minutes. However, at the hospital level, a minority of hospitals (49%) reliably achieved the OAR goal door-to-intervention time. For OARs, there was no difference in 30-day risk-adjusted major complications or mortality between the ≤90- and > 90-minute cohorts. For EVAR, 1014 patients (53.8%) had a door-to-intervention time of ≤90 minutes and a minority of hospitals (40%) upheld the recommended ≤90 minute door-to-intervention threshold. In the EVAR group, patients with a ≤90 minute door-to-intervention time had higher rates of postoperative myocardial infarction (12.0% vs. 8.5%; P < 0.05) but no difference in 30-day risk-adjusted mortality.

Conclusions: A low percentage of rAAAs are being treated within the recommended door-to-intervention time. Despite this deficiency, the ≤90-minute benchmark has minimal impact on postoperative morbidity and mortality. Based on these findings, alternative quality metrics should be identified to improve the clinical care of patients with rAAA.
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http://dx.doi.org/10.1016/j.avsg.2019.05.009DOI Listing
January 2020

The Predictive Performance of a Pneumonia Severity Score in Human Immunodeficiency Virus-negative Children Presenting to Hospital in 7 Low- and Middle-income Countries.

Clin Infect Dis 2020 03;70(6):1050-1057

Department of Infectious Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, United Kingdom.

Background: In 2015, pneumonia remained the leading cause of mortality in children aged 1-59 months.

Methods: Data from 1802 human immunodeficiency virus (HIV)-negative children aged 1-59 months enrolled in the Pneumonia Etiology Research for Child Health (PERCH) study with severe or very severe pneumonia during 2011-2014 were used to build a parsimonious multivariable model predicting mortality using backwards stepwise logistic regression. The PERCH severity score, derived from model coefficients, was validated on a second, temporally discrete dataset of a further 1819 cases and compared to other available scores using the C statistic.

Results: Predictors of mortality, across 7 low- and middle-income countries, were age <1 year, female sex, ≥3 days of illness prior to presentation to hospital, low weight for height, unresponsiveness, deep breathing, hypoxemia, grunting, and the absence of cough. The model discriminated well between those who died and those who survived (C statistic = 0.84), but the predictive capacity of the PERCH 5-stratum score derived from the coefficients was moderate (C statistic = 0.76). The performance of the Respiratory Index of Severity in Children score was similar (C statistic = 0.76). The number of World Health Organization (WHO) danger signs demonstrated the highest discrimination (C statistic = 0.82; 1.5% died if no danger signs, 10% if 1 danger sign, and 33% if ≥2 danger signs).

Conclusions: The PERCH severity score could be used to interpret geographic variations in pneumonia mortality and etiology. The number of WHO danger signs on presentation to hospital could be the most useful of the currently available tools to aid clinical management of pneumonia.
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http://dx.doi.org/10.1093/cid/ciz350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610754PMC
March 2020

Medical and Psychological Considerations for Carbohydrate-Restricted Diets in Youth With Type 1 Diabetes.

Curr Diab Rep 2019 04 27;19(6):27. Epub 2019 Apr 27.

Baylor College of Medicine and Texas Children's Hospital, 1102 Bates Ave, Suite 940, Houston, TX, 77030, USA.

Purpose Of Review: Given the challenges achieving recommended glycemic targets in youth with type 1 diabetes (T1D), providers may consider recommending carbohydrate-restricted diets (CRDs) to optimize glycemic control. The goal of the present review is to describe relevant literature on the potential medical and psychosocial benefits and risks of CRDs in youth with T1D.

Recent Findings: Limited data exist on the effects of CRDs in pediatric populations. Findings from studies with youth and adults are mixed; some indicate that CRDs may be associated with desirable medical outcomes, such as improved glycemic control and reduced HbA1c, which may contribute to positive psychological outcomes such as reduced diabetes distress and depressive symptoms. Others suggest that CRDs may also be associated with detrimental outcomes, including mineral deficiencies and suboptimal growth, and dietary restriction has been linked to greater diabetes distress, disordered eating, and diabetes management. More research is needed to evaluate benefits and risks of CRDs in youth. Providers should exercise caution when discussing CRDs with youth and families, particularly when considering CRDs for youth at elevated risk for eating disordered behavior.
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http://dx.doi.org/10.1007/s11892-019-1153-2DOI Listing
April 2019

Association of Peritumoral Radiomics With Tumor Biology and Pathologic Response to Preoperative Targeted Therapy for HER2 (ERBB2)-Positive Breast Cancer.

JAMA Netw Open 2019 04 5;2(4):e192561. Epub 2019 Apr 5.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio.

Importance: There has been significant recent interest in understanding the utility of quantitative imaging to delineate breast cancer intrinsic biological factors and therapeutic response. No clinically accepted biomarkers are as yet available for estimation of response to human epidermal growth factor receptor 2 (currently known as ERBB2, but referred to as HER2 in this study)-targeted therapy in breast cancer.

Objective: To determine whether imaging signatures on clinical breast magnetic resonance imaging (MRI) could noninvasively characterize HER2-positive tumor biological factors and estimate response to HER2-targeted neoadjuvant therapy.

Design, Setting, And Participants: In a retrospective diagnostic study encompassing 209 patients with breast cancer, textural imaging features extracted within the tumor and annular peritumoral tissue regions on MRI were examined as a means to identify increasingly granular breast cancer subgroups relevant to therapeutic approach and response. First, among a cohort of 117 patients who received an MRI prior to neoadjuvant chemotherapy (NAC) at a single institution from April 27, 2012, through September 4, 2015, imaging features that distinguished HER2+ tumors from other receptor subtypes were identified. Next, among a cohort of 42 patients with HER2+ breast cancers with available MRI and RNaseq data accumulated from a multicenter, preoperative clinical trial (BrUOG 211B), a signature of the response-associated HER2-enriched (HER2-E) molecular subtype within HER2+ tumors (n = 42) was identified. The association of this signature with pathologic complete response was explored in 2 patient cohorts from different institutions, where all patients received HER2-targeted NAC (n = 28, n = 50). Finally, the association between significant peritumoral features and lymphocyte distribution was explored in patients within the BrUOG 211B trial who had corresponding biopsy hematoxylin-eosin-stained slide images. Data analysis was conducted from January 15, 2017, to February 14, 2019.

Main Outcomes And Measures: Evaluation of imaging signatures by the area under the receiver operating characteristic curve (AUC) in identifying HER2+ molecular subtypes and distinguishing pathologic complete response (ypT0/is) to NAC with HER2-targeting.

Results: In the 209 patients included (mean [SD] age, 51.1 [11.7] years), features from the peritumoral regions better discriminated HER2-E tumors (maximum AUC, 0.85; 95% CI, 0.79-0.90; 9-12 mm from the tumor) compared with intratumoral features (AUC, 0.76; 95% CI, 0.69-0.84). A classifier combining peritumoral and intratumoral features identified the HER2-E subtype (AUC, 0.89; 95% CI, 0.84-0.93) and was significantly associated with response to HER2-targeted therapy in both validation cohorts (AUC, 0.80; 95% CI, 0.61-0.98 and AUC, 0.69; 95% CI, 0.53-0.84). Features from the 0- to 3-mm peritumoral region were significantly associated with the density of tumor-infiltrating lymphocytes (R2 = 0.57; 95% CI, 0.39-0.75; P = .002).

Conclusions And Relevance: A combination of peritumoral and intratumoral characteristics appears to identify intrinsic molecular subtypes of HER2+ breast cancers from imaging, offering insights into immune response within the peritumoral environment and suggesting potential benefit for treatment guidance.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.2561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481453PMC
April 2019

Introducing an AKI predictive tool for patients undergoing orthopaedic surgery.

BMJ Open Qual 2019 29;8(1):e000306. Epub 2019 Mar 29.

Renal Medicine, Ninewells Hospital, Dundee, UK.

Patients undergoing surgery are at increased risk of acute kidney injury (AKI). AKI is associated with adverse outcomes such as increased mortality and future risk of developing chronic kidney disease. We have developed a validated preoperative scoring tool to predict postoperative AKI in patients undergoing orthopaedic surgery using seven readily available parameters. The aim of this project was to establish the use of this scoring tool with a target compliance of 80% in patients undergoing orthopaedic surgery requiring an overnight stay at Perth Royal Infirmary, a district general hospital in NHS Tayside. We created an intervention bundle for patients at high risk of AKI, which we defined as greater than 10%. An electronic tool available on smartphones and desktop computers was developed that can be used to calculate the score. The interventions were incorporated into the electronic tool and posters outlining the intervention were placed in clinical areas. Patients undergoing elective procedures were scored in the preassessment clinic while emergency patients were scored by the admitting doctors. The score was introduced using four PDSA cycles. This confirmed that the scoring tool functioned well and was being used accurately. Compliance for patients undergoing elective surgery was reasonable at 19/24 (79%) in the third and fourth PDSA cycles but was poorer for emergency admissions with compliance of only 3/7 (43%). There was excellent compliance with the suggested medication changes and postoperative blood test monitoring as advised by our intervention bundle for those at high risk of AKI. Fluid balance monitoring was advised for all patients but the outcome was similar following our intervention at 27/41 (66%) compared with 23/37 (62%) in the baseline data collection. Compliance with fluid balance monitoring was higher in patients at high risk of AKI (9/12, 75%).
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http://dx.doi.org/10.1136/bmjoq-2017-000306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440603PMC
April 2020

Validation of the UCLA PTSD Reaction Index for DSM-5: A Developmentally Informed Assessment Tool for Youth.

J Am Acad Child Adolesc Psychiatry 2020 01 3;59(1):186-194. Epub 2019 Apr 3.

University of California, Los Angeles (UCLA); UCLA and the Duke University National Center for Child Traumatic Stress, Durham, NC.

Objective: To describe the test construction procedure and evaluate the internal consistency, criterion-referenced validity, and diagnostic accuracy of the Child/Adolescent Self-Report Version of the UCLA PTSD Reaction Index for DSM-5 (RI-5) across 2 independent samples.

Method: Study 1 examined the clarity, developmental appropriateness, acceptability of individual RI-5 items, and internal consistency and criterion-referenced validity of the full test. The study 1 sample included 486 youth recruited from 2 major US cities who completed the RI-5 and a measure of depression. Study 2 evaluated the reliability and diagnostic accuracy of the RI-5 in 41 treatment-seeking youth who completed the RI-5 and a "gold standard" structured diagnostic interview, the Clinician-Administered PTSD Scale for DSM-5-Child/Adolescent Version.

Results: RI-5 total scale scores showed excellent internal consistency in the 2 samples. Study 1 provided evidence of criterion-referenced validity, in that total scale scores correlated positively with depressive symptoms. Study 2 provided evidence of diagnostic accuracy (including discriminant-groups validity). RI-5 total scores discriminated youth with from youth without PTSD as benchmarked against the structured diagnostic interview. Further, receiver operating characteristic analyses using a total score of 35 provided excellent diagnostic classification accuracy (area under the curve 0.94).

Conclusion: The developmental appropriateness and diagnostic accuracy of the RI-5 support its utility for clinical assessment, case conceptualization, and treatment planning in different child-serving systems, including schools, juvenile justice, child welfare, and mental health.
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http://dx.doi.org/10.1016/j.jaac.2018.10.019DOI Listing
January 2020

Characterization of Sub-1 cm Breast Lesions Using Radiomics Analysis.

J Magn Reson Imaging 2019 11 27;50(5):1468-1477. Epub 2019 Mar 27.

Breast Imaging Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Background: Small breast lesions are difficult to visually categorize due to the inherent lack of morphological and kinetic detail.

Purpose: To assess the efficacy of radiomics analysis in discriminating small benign and malignant lesions utilizing model free parameter maps.

Study Type: Retrospective, single center.

Population: In all, 149 patients, with a total of 165 lesions scored as BI-RADS 4 or 5 on MRI, with an enhancing volume of <0.52 cm .

Field Strength/sequence: Higher spatial resolution T -weighted dynamic contrast-enhanced imaging with a temporal resolution of ~90 seconds performed at 3.0T.

Assessment: Parameter maps reflecting initial enhancement, overall enhancement, area under the enhancement curve, and washout were generated. Heterogeneity measures based on first-order statistics, gray level co-occurrence matrices, run length matrices, size zone matrices, and neighborhood gray tone difference matrices were calculated. Data were split into a training dataset (~75% of cases) and a test dataset (~25% of cases).

Statistical Tests: Comparison of medians was assessed using the nonparametric Mann-Whitney U-test. The Spearman rank correlation coefficient was utilized to determine significant correlations between individual features. Finally, a support vector machine was employed to build multiparametric predictive models.

Results: Univariate analysis revealed significant differences between benign and malignant lesions for 58/133 calculated features (P < 0.05). Support vector machine analysis resulted in areas under the curve (AUCs) ranging from 0.75-0.81. High negative (>89%) and positive predictive values (>83%) were found for all models.

Data Conclusion: Radiomics analysis of small contrast-enhancing breast lesions is of value. Texture features calculated from later timepoints on the enhancement curve appear to offer limited additional value when compared with features determined from initial enhancement for this patient cohort.

Level Of Evidence: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1468-1477.
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http://dx.doi.org/10.1002/jmri.26732DOI Listing
November 2019