Publications by authors named "Mark Anderson"

795 Publications

Clinical impact of PET/MRI in oligometastatic colorectal cancer.

Br J Cancer 2021 Jul 19. Epub 2021 Jul 19.

Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background: Oligometastatic colorectal cancer (CRC) is potentially curable and demands individualised strategies.

Methods: This single-centre retrospective study investigated if positron emission tomography (PET)/magnetic resonance imaging (MR) had a clinical impact on oligometastatic CRC relative to the standard of care imaging (SCI). Adult patients with oligometastatic CRC on SCI who also underwent PET/MR between 3/2016 and 3/2019 were included. The exclusion criterion was lack of confirmatory standard of reference, either surgical pathology, intraoperative gross confirmation or imaging follow-up. SCI consisted of contrast-enhanced (CE) computed tomography (CT) of the chest/abdomen/pelvis, abdominal/pelvic CE-MR, and/or CE whole-body PET/CT with diagnostic quality (i.e. standard radiation dose) CT. Follow-up was evaluated until 3/2020.

Results: Thirty-one patients constituted the cohort, 16 (52%) male, median patient age was 53 years (interquartile range: 49-65 years). PET/MR and SCI results were divergent in 19% (95% CI 9-37%) of the cases, with PET/MR leading to management changes in all of them. The diagnostic accuracy of PET/MR was 90 ± 5%, versus 71 ± 8% for SCI. In a pairwise analysis, PET/MR outperformed SCI when compared to the reference standard (p = 0.0412).

Conclusions: These findings suggest the potential usefulness of PET/MR in the management of oligometastatic CRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-021-01494-8DOI Listing
July 2021

Extrathymic -expressing cells support maternal-fetal tolerance.

Sci Immunol 2021 Jul;6(61)

Department of Surgery, University of California, San Francisco, CA, USA.

Healthy pregnancy requires tolerance to fetal alloantigens as well as syngeneic embryonic and placental antigens. Given the importance of the autoimmune regulator () gene in self-tolerance, we investigated the role of -expressing cells in maternal-fetal tolerance. We report that maternal ablation of -expressing ( ) cells during early mouse pregnancy caused intrauterine growth restriction (IUGR) in both allogeneic and syngeneic pregnancies. This phenotype is immune mediated, as IUGR was rescued in Rag1-deficient mice, and involved a memory response, demonstrated by recurrence of severe IUGR in second pregnancies. Single-cell RNA sequencing demonstrated that cell depletion in pregnancy results in expansion of activated T cells, particularly T follicular helper cells. Unexpectedly, selective ablation of either -expressing medullary thymic epithelial cells or extrathymic -expressing cells (eTACs) mapped the IUGR phenotype exclusively to eTACs. Thus, we report a previously undescribed mechanism for the maintenance of maternal-fetal immune homeostasis and demonstrate that eTACs protect the conceptus from immune-mediated IUGR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciimmunol.abf1968DOI Listing
July 2021

Replication Dynamics for Six Gram-Negative Bacterial Species during Bloodstream Infection.

mBio 2021 Jul 6:e0111421. Epub 2021 Jul 6.

University of Michigan Medical School, Department of Microbiology and Immunology, Ann Arbor, Michigan, USA.

Bloodstream infections (BSI) are a major public health burden due to high mortality rates and the cost of treatment. The impact of BSI is further compounded by a rise in antibiotic resistance among Gram-negative species associated with these infections. Escherichia coli, Serratia marcescens, Klebsiella pneumoniae, Enterobacter hormaechei, Citrobacter freundii, and Acinetobacter baumannii are all common causes of BSI, which can be recapitulated in a murine model. The objective of this study was to characterize infection kinetics and bacterial replication rates during bacteremia for these six pathogens to gain a better understanding of bacterial physiology during infection. Temporal observations of bacterial burdens of the tested species demonstrated varied abilities to establish colonization in the spleen, liver, or kidney. K. pneumoniae and S. marcescens expanded rapidly in the liver and kidney, respectively. Other organisms, such as C. freundii and E. hormaechei, were steadily cleared from all three target organs throughout the infection. replication rates measured by whole-genome sequencing of bacterial DNA recovered from murine spleens demonstrated that each species was capable of sustained replication at 24 h postinfection, and several species demonstrated <60-min generation times. The relatively short generation times observed in the spleen were in contrast to an overall decrease in bacterial burden for some species, suggesting that the rate of immune-mediated clearance exceeded replication. Furthermore, bacterial generation times measured in the murine spleen approximated those measured during growth in human serum cultures. Together, these findings provide insight into the infection kinetics of six medically important species during bacteremia. Bloodstream infections are a global public health problem. The goal of this work was to determine the replication characteristics of Gram-negative bacterial species in the host following bloodstream infection. The number of bacteria in major organs is likely determined by a balance between replication rates and the ability of the host to clear bacteria. We selected a cohort of six species from three families that represent common causative agents of bloodstream infections in humans and determined their replication rates in a murine bacteremia model. We found that the bacteria grow rapidly in the spleen, demonstrating that they can obtain the necessary nutrients for growth in this environment. However, the overall number of bacteria decreased in most cases, suggesting that killing of bacteria outpaces their growth. Through a better understanding of how bacteria replicate during bloodstream infections, we aim to gain insight into future means of combating these infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mBio.01114-21DOI Listing
July 2021

SATB2 Immunoexpression in Peripheral Ossifying Fibroma and Peripheral Odontogenic Fibroma.

Head Neck Pathol 2021 Jul 5. Epub 2021 Jul 5.

Department of Diagnostic Sciences, University of Tennessee Health Science Center, College of Dentistry, 875 Union Avenue, Memphis, TN, 38163, USA.

Peripheral ossifying fibromas (POFs) and peripheral odontogenic fibromas (POdFs) appear clinically similar but of different histogenesis. The novel marker SATB2 is involved in regulation of osteoblastic differentiation and phenotype. However, SATB2 expression has not been previously explored in POFs and POdFs. Given the potential for mineralized tissue formation in POFs and POdFs, and to more clarify the phenotype of the lesional cells, this study was aimed to immunohistochemically investigate SATB2 expression in POFs and POdFs. Fourteen cases of POF and POdF (7 cases each) were selected, stained for SATB2 immunohistochemically, and scored according to the percentage of positive lesional cells (0, no staining; 1 +, < 5%; 2 +, 5-25%; 3 +, 26-50%; 4 +, 51-75%; and 5 +, 76-100%), and the intensity of staining was graded as weak, moderate, or strong. The control group included the inflammatory fibrous hyperplasia-like area present in two cases, 1 case fibroma, and 1 case giant cell fibroma. Moderate to strong, and diffuse SATB2 nuclear immunoreactivity was detected in the lesional cells of all cases of POFs and POdFs with variable scores; 3-5 + for the POFs and 3-4 + for the POdFs (P = 0.101). The distribution of staining was more prominent in those lesional cells associated with the osteoid/calcification in the cases of POFs. No staining was noted in the control group. The lesional cells in both POFs and POdFs express SATB2 and may exhibit the osteoblastic-like phenotype. SATB2 staining may be useful for diagnosis of subsets of POFs with minimal or absent calcification and some POdFs with unidentifiable odontogenic epithelium.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12105-021-01355-zDOI Listing
July 2021

Diabetes With Multiple Autoimmune and Inflammatory Conditions Linked to an Activating SKAP2 Mutation.

Diabetes Care 2021 Jun 25. Epub 2021 Jun 25.

Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA

Objective: Multiple genome-wide association studies have identified a strong genetic linkage between the locus and type 1 diabetes (T1D), but how this leads to disease remains obscure. Here, we characterized the functional consequence of a novel coding mutation in a patient with T1D to gain further insight into how this impacts immune tolerance.

Research Design And Methods: We identified a 24-year-old individual with T1D and other autoimmune and inflammatory conditions. The proband and first-degree relatives were recruited for whole-exome sequencing. Functional studies of the protein variant were performed using a cell line and primary myeloid immune cells collected from family members.

Results: Sequencing identified a de novo variant (c.457G>A, p.Gly153Arg) in the proband. Assays using monocyte-derived macrophages from the individual revealed enhanced activity of integrin pathways and a migratory phenotype in the absence of chemokine stimulation, consistent with SKAP2 p.Gly153Arg being constitutively active. The p.Gly153Arg variant, located in the well-conserved lipid-binding loop, induced similar phenotypes when expressed in a human macrophage cell line. SKAP2 p.Gly153Arg is a gain-of-function, pathogenic mutation that disrupts myeloid immune cell function, likely resulting in a break in immune tolerance and T1D.

Conclusions: SKAP2 plays a key role in myeloid cell activation and migration. This particular mutation in a patient with T1D and multiple autoimmune conditions implicates a role for activating variants in autoimmune T1D.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc20-2317DOI Listing
June 2021

Expanding access to SARS-CoV-2 IgG and IgM serologic testing using fingerstick whole blood, plasma, and rapid lateral flow assays.

J Clin Virol 2021 May 11;141:104855. Epub 2021 May 11.

Abbott Laboratories, Abbott Diagnostics Division, 100 Abbott Park Road, Bldg. AP20, Abbott Park, IL 60064-3500, United States. Electronic address:

Serologic testing for SARS-CoV-2 antibodies can be used to confirm diagnosis, estimate seroprevalence, screen convalescent plasma donors, and assess vaccine efficacy. Dried blood spot (DBS) samples have been used for serology testing of various diseases in resource-limited settings. We examined the use of DBS samples and capillary blood (fingerstick) plasma collected in Microtainer tubes for SARS-CoV-2 testing with the automated Abbott ARCHITECT™ SARS-CoV-2 IgG and IgM assays and use of venous whole blood with a prototype PANBIO™ rapid point-of-care lateral flow SARS-CoV-2 IgG assay. The ARCHITECT™ SARS-CoV-2 IgG assay was initially optimized for use with DBS, venous and capillary plasma, and venous whole blood collected from patients with symptoms and PCR-confirmed COVID-19 and negative asymptomatic controls. Linearity and reproducibility was confirmed with 3 contrived DBS samples, along with sample stability and signal recovery after 14 days. ARCHITECT™ SARS-CoV-2 IgG and IgM assay results showed high concordance between fingerstick DBS and venous DBS samples, and between fingerstick DBS and venous whole blood samples (n = 61). Fingerstick plasma collected in Microtainer tubes (n = 109) showed 100% concordant results (R=0.997) with matched patient venous plasma on the ARCHITECT™ SARS-CoV-2 IgG assay. High concordance of assay results (92.9% positive, 100% negative) was also observed for the PANBIO™ SARS-CoV-2 IgG assay compared to the ARCHITECT™ SARS-CoV-2 IgG assay run with matched venous plasma (n = 61). Fingerstick DBS and plasma samples are easy and inexpensive to collect and, along with the use of rapid point-of-care testing platforms, will expand access to SARS-CoV-2 serology testing, particularly in resource-limited areas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcv.2021.104855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111886PMC
May 2021

A human mutation in STAT3 promotes type 1 diabetes through a defect in CD8+ T cell tolerance.

J Exp Med 2021 Aug 11;218(8). Epub 2021 Jun 11.

Diabetes Center, University of California, San Francisco, San Francisco, CA.

Naturally occurring cases of monogenic type 1 diabetes (T1D) help establish direct mechanisms driving this complex autoimmune disease. A recently identified de novo germline gain-of-function (GOF) mutation in the transcriptional regulator STAT3 was found to cause neonatal T1D. We engineered a novel knock-in mouse incorporating this highly diabetogenic human STAT3 mutation (K392R) and found that these mice recapitulated the human autoimmune diabetes phenotype. Paired single-cell TCR and RNA sequencing revealed that STAT3-GOF drives proliferation and clonal expansion of effector CD8+ cells that resist terminal exhaustion. Single-cell ATAC-seq showed that these effector T cells are epigenetically distinct and have differential chromatin architecture induced by STAT3-GOF. Analysis of islet TCR clonotypes revealed a CD8+ cell reacting against known antigen IGRP, and STAT3-GOF in an IGRP-reactive TCR transgenic model demonstrated that STAT3-GOF intrinsic to CD8+ cells is sufficient to accelerate diabetes onset. Altogether, these findings reveal a diabetogenic CD8+ T cell response that is restrained in the presence of normal STAT3 activity and drives diabetes pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1084/jem.20210759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203485PMC
August 2021

ABBV-176, a PRLR antibody drug conjugate with a potent DNA-damaging PBD cytotoxin and enhanced activity with PARP inhibition.

BMC Cancer 2021 Jun 9;21(1):681. Epub 2021 Jun 9.

AbbVie Inc., Oncology Discovery, 1 North Waukegan Rd., North Chicago, IL, 60064-6099, USA.

Background: Prolactin receptor (PRLR) is an attractive antibody therapeutic target with expression across a broad population of breast cancers. Antibody efficacy, however, may be limited to subtypes with either PRLR overexpression and/or those where estradiol no longer functions as a mitogen and are, therefore, reliant on PRLR signaling for growth. In contrast a potent PRLR antibody-drug conjugate (ADC) may provide improved therapeutic outcomes extending beyond either PRLR overexpressing or estradiol-insensitive breast cancer populations.

Methods: We derived a novel ADC targeting PRLR, ABBV-176, that delivers a pyrrolobenzodiazepine (PBD) dimer cytotoxin, an emerging class of warheads with enhanced potency and broader anticancer activity than the clinically validated auristatin or maytansine derivatives. This agent was tested in vitro and in vivo cell lines and patient derived xenograft models.

Results: In both in vitro and in vivo assays, ABBV-176 exhibits potent cytotoxicity against multiple cell line and patient-derived xenograft breast tumor models, including triple negative and low PRLR expressing models insensitive to monomethyl auristatin (MMAE) based PRLR ADCs. ABBV-176, which cross links DNA and causes DNA breaks by virtue of its PBD warhead, also demonstrates enhanced anti-tumor activity in several breast cancer models when combined with a poly-ADP ribose polymerase (PARP) inhibitor, a potentiator of DNA damage.

Conclusions: Collectively the efficacy and safety profile of ABBV-176 suggest it may be an effective therapy across a broad range of breast cancers and other cancer types where PRLR is expressed with the potential to combine with other therapeutics including PARP inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-021-08403-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191021PMC
June 2021

Early Outcomes of the First 200 US Patients Treated with Impella 5.5: A Novel Temporary Left Ventricular Assist Device.

Innovations (Phila) 2021 Jun 8:15569845211013329. Epub 2021 Jun 8.

2569 Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, OH, USA.

Objective: To report the initial clinical experience with the Impella 5.5 with SmartAssist, a temporary left ventricular assist device that provides up to 6.2 L/min forward flow, with recent FDA approval for up to 14 days.

Methods: From October 2019 to March 2020, 200 patients at 42 US centers received the Impella 5.5 and entered into the IQ registry, a manufacturer-maintained quality database that captures limited baseline/procedural characteristics and outcomes through device explant. Post hoc subgroup analyses were conducted to assess the role of baseline and procedural characteristics on survival, defined as successful device weaning or bridge to durable therapy.

Results: Median patient age was 62 years (range, 13 to 83 years); 83.4% were male. The device was most commonly used for cardiomyopathy (45.0%), acute myocardial infarction complicated by cardiogenic shock (AMICS; 29.0%), and post cardiotomy cardiogenic shock (PCCS; 16.5%). Median duration of support was 10.0 days (range, 0.001 to 64.4 days). Through device explant, overall survival was 74.0%, with survival of 80.0%, 67.2%, 57.6%, and 94.7% in cardiomyopathy, AMICS, PCCS, and others (comprising high-risk revascularization, coronary artery bypass graft, electrophysiology/ablation, and myocarditis), respectively. Patients requiring extracorporeal membrane oxygenation and Impella support (35 patients, 17.5%) had significantly lower survival (51.4% vs 78.8%, = 0.002).

Conclusions: In the first 200 US patients treated with the Impella 5.5, we observed overall survival to explant of 74%. Survival outcomes were improved compared to historic rates observed with cardiogenic shock, particularly PCCS. Prospective studies assessing comparative performance of this device to conventional strategies are warranted in future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/15569845211013329DOI Listing
June 2021

Targeting Central Nervous System Regeneration with Cell Type Specificity.

Authors:
Mark A Anderson

Neurosurg Clin N Am 2021 Jul 11;32(3):397-405. Epub 2021 May 11.

Brain Mind Institute, Faculty of Life Sciences, École Polytechnique Féderale de Lausanne (EPFL), Lausanne, Switzerland; Neural Repair Unit, NeuroRestore, Department of Clinical Neuroscience, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland. Electronic address:

There have been tremendous advances in identifying cellular and molecular mechanisms constraining axon growth and strategies have been developed to overcome regenerative failure. However, reproducible and meaningful functional recovery remains elusive. An emerging reason is that neurons possess subtype-specific activation requirements. Much of this evidence comes from studying retinal ganglion cells following optic nerve injury. This review summarizes key neuropathologic events following spinal cord injury, and draws on findings from the optic nerve to suggest how a similar framework may be used to dissect and manipulate the heterogeneous and subtype-specific responses of neurons useful to target for spinal cord injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nec.2021.03.011DOI Listing
July 2021

Immunogenicity of a first dose of mRNA- or vector-based SARS-CoV-2 vaccination in dialysis patients: a multicenter prospective observational pilot study.

J Nephrol 2021 May 29. Epub 2021 May 29.

Diaverum Renal Care Center, 14469, Potsdam, Germany.

Background: Dialysis patients are at risk for lower SARS-CoV-2-vaccine immunogenicity than the normal population. We assessed immunogenicity to a first mRNA- or vector-based SARS-CoV-2-vaccination dose in dialysis patients.

Methods: In a multicenter observational pilot study, 2 weeks after a first vaccination (BNT162b2/Pfizer-BioNTech [Comirnaty] or ChAdOx1 nCoV-19/Oxford-Astra-Zeneca [Vaxzevria]), hemodialysis patients (N = 23), peritoneal dialysis patients (N = 4) and healthy staff (N = 14) were tested for SARS-CoV-2-spike IgG/IgM, Nucleocapsid-protein-IgG-antibodies and plasma ACE2-receptor-binding-inhibition capacity. Hemodialysis patients who had had prior COVID-19 infection (N = 18) served as controls. Both response to first SARS-CoV-2 vaccination and IgG spike-positivity following prior COVID-19 infection were defined as SARS-CoV-2 spike IgG levels ≥ 50 AU/mL.

Results: Vaccination responder rates were 17.4% (4/23) in hemodialysis patients, 100% (4/4) in peritoneal dialysis patients and 57.1% (8/14) in staff (HD vs. PD: p = 0.004, HD vs. staff: p = 0.027). Among hemodialysis patients, type of vaccine (Comirnaty N = 11, Vaxzevria N = 12, 2 responders each) did not appear to influence antibody levels (IgG spike: Comirnaty median 0.0 [1.-3. quartile 0.0-3.8] versus Vaxzevria 4.3 [1.6-20.1] AU/mL, p = 0.079). Of responders to the first dose of SARS-CoV-2 vaccination among hemodialysis patients (N = 4/23), median IgG spike levels and ACE2-receptor-binding-inhibition capacity were lower than that of IgG spike-positive hemodialysis patients with prior COVID-19 infection (13/18, 72.2%): IgG spike: median 222.0, 1.-3. quartile 104.1-721.9 versus median 3794.6, 1.-3. quartile 793.4-9357.9 AU/mL, p = 0.015; ACE2-receptor-binding-inhibition capacity: median 11.5%, 1.-3. quartile 5.0-27.3 versus median 74.8%, 1.-3. quartile 44.9-98.1, p = 0.002.

Conclusions: Two weeks after their first mRNA- or vector-based SARS-CoV-2 vaccination, hemodialysis patients demonstrated lower antibody-related response than peritoneal dialysis patients and healthy staff or unvaccinated hemodialysis patients following prior COVID-19 infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40620-021-01076-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164063PMC
May 2021

CaMKII oxidation is a critical performance/disease trade-off acquired at the dawn of vertebrate evolution.

Nat Commun 2021 05 26;12(1):3175. Epub 2021 May 26.

Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Antagonistic pleiotropy is a foundational theory that predicts aging-related diseases are the result of evolved genetic traits conferring advantages early in life. Here we examine CaMKII, a pluripotent signaling molecule that contributes to common aging-related diseases, and find that its activation by reactive oxygen species (ROS) was acquired more than half-a-billion years ago along the vertebrate stem lineage. Functional experiments using genetically engineered mice and flies reveal ancestral vertebrates were poised to benefit from the union of ROS and CaMKII, which conferred physiological advantage by allowing ROS to increase intracellular Ca and activate transcriptional programs important for exercise and immunity. Enhanced sensitivity to the adverse effects of ROS in diseases and aging is thus a trade-off for positive traits that facilitated the early and continued evolutionary success of vertebrates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-23549-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155201PMC
May 2021

Long-term Outcomes of Delayed Scapholunate Ligament Repair After Complete Rupture of the Ligament.

Orthopedics 2021 May-Jun;44(3):e446-e453. Epub 2021 May 1.

Treatment of isolated complete tear of the scapholunate ligament is challenging. The purpose of this study was to determine (1) whether delayed repair of only scapholunate ligament is an option without other reconstruction procedures and (2) whether functional outcomes are possible despite radiographic presence of arthritis. This study included patients who had complete ligament tear at exploration and underwent only scapholunate ligament repair without capsulodesis or tenodesis. Fifteen patients returned for clinical and radiographic examinations. Preoperatively, mean scapholunate gap was 2.9 mm and 4.58 mm on posteroanterior and tangential posteroanterior views, respectively. Postoperatively, the final mean gap was 2.5 mm and 3.9 mm on the posteroanterior and tangential posteroanterior views, respectively. The mean preoperative and final scapholunate angles were 74° and 72.6°, respectively. Seven patients had radiographic arthritis at final follow-up. Delayed scapholunate repair is possible after complete ligament tear. At long-term follow-up, clinical functional outcomes may not correlate with radiographic presence of degenerative arthritis. [. 2021;44(3):e446-e453.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3928/01477447-20210415-04DOI Listing
July 2021

A Targeted Geospatial Approach to COVID-19 Vaccine Delivery: Findings from the Johns Hopkins Hospital Emergency Department.

medRxiv 2021 May 10. Epub 2021 May 10.

While COVID-19 vaccines have been shown to significantly decrease morbidity and mortality, there is still much debate about optimal strategies of vaccine rollout. We tested identity-unlinked stored remnant blood specimens of patients at least 18 years presenting to the Johns Hopkins Hospital emergency department (ED) between May to November 2020 for IgG to SARS-CoV-2. Data on SARS-CoV-2 RT PCR were available for patients who were tested due to suspected infection. SARS-CoV-2 infections was defined as either a positive IgG and/or RT-PCR. SARS-CoV-2 infection clustering by zipcode was analyzed by spatial analysis using the Bernoulli model (SaTScan software, Version 9.7). Median age of the 7,461 unique patients visiting the ED was 47 years and 50.8% were female; overall, 740 (9.9%) unique patients had evidence of SARS-CoV-2 infection. Prevalence of infection in ED patients by ZIP code ranged from 4.1% to 22.3%. The observed number of cases in ZIP code C was nearly double the expected (observed/expected ratio = 1.99; 95% CI: 1.62, 2.42). These data suggest a targeted geospatial approach to COVID vaccination should be considered to maximize vaccine rollout efficiency and include high-risk populations that may otherwise be subjected to delays, or missed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2021.05.04.21255575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132280PMC
May 2021

Single-cell transcriptome analysis defines heterogeneity of the murine pancreatic ductal tree.

Elife 2021 May 19;10. Epub 2021 May 19.

Diabetes Center, University of California, San Francisco, San Francisco, United States.

To study disease development, an inventory of an organ's cell types and understanding of physiologic function is paramount. Here, we performed single-cell RNA-sequencing to examine heterogeneity of murine pancreatic duct cells, pancreatobiliary cells, and intrapancreatic bile duct cells. We describe an epithelial-mesenchymal transitory axis in our three pancreatic duct subpopulations and identify osteopontin as a regulator of this fate decision as well as human duct cell dedifferentiation. Our results further identify functional heterogeneity within pancreatic duct subpopulations by elucidating a role for geminin in accumulation of DNA damage in the setting of chronic pancreatitis. Our findings implicate diverse functional roles for subpopulations of pancreatic duct cells in maintenance of duct cell identity and disease progression and establish a comprehensive road map of murine pancreatic duct cell, pancreatobiliary cell, and intrapancreatic bile duct cell homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.67776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184217PMC
May 2021

Impact of surgical volume and resident involvement on patency rates after vasectomy reversal-A 14-year experience in an open access system.

Asian J Urol 2021 Apr 23;8(2):197-203. Epub 2020 Apr 23.

Division of Urology, Duke University Hospital, Durham, NC, USA.

Objective: Evaluate the influence of fellowship training, resident participation, reconstruction type, and patient factors on outcomes after vasectomy reversals in a high volume, open access system.

Methods: Retrospective review of all vasectomy reversals performed at a single institution from January 1, 2002 to December 31, 2016 was conducted. Patient and spouse demographics, patient tobacco use and comorbidities, surgeon training and case volume, resident participation, reconstruction type, and postoperative patency were collected and analyzed.

Results: Five hundred and twenty-six vasectomy reversals were performed during the study period. Follow-up was available in 80.6% of the cohort and overall patency, regardless of reconstruction type was 88.7%. The mean time to reversal was 7.87 years (range of 0-34 years). The majority of cases included resident participation. Case volume was high with faculty and residents logging a mean of 37.0 and 38.7 (median 18 and 37) cases respectively. Bilateral vasovasostomy was the most common reconstruction type (83%) and demonstrated a significantly better patency rate (89%) than all other reconstructions (=0.0008). Overall patency and patency by reconstruction type were not statistically different among faculty surgeons and were not impacted by fertility fellowship training, resident participation or post-graduate year. Multivariate analysis demonstrated that increased time to reversal and repeat reconstructions had a negative impact on patency (=0.0023 and =0.043, respectively).

Conclusions: Surgeons with a high volume of vasectomy reversals have outcomes consistent with contemporary series regardless of fellowship training in fertility. Patency was better for bilateral vasovasostomies. Patency was not negatively impacted by tobacco use, comorbidities, resident participation, or post-graduate year.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajur.2020.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099639PMC
April 2021

The phenomenon of summer diarrhea and its waning, 1910-1930.

Explor Econ Hist 2020 Oct 19;78. Epub 2020 Jun 19.

Department of Economics, University of Pittsburgh.

During the first two decades of the 20 century, diarrheal deaths among American infants and children surged every summer. Although we still do not know what pathogen (or pathogens) caused this phenomenon, the consensus view is that it was eventually controlled through public health efforts at the municipal level. Using data from 26 major American cities for the period 1910-1930, we document the phenomenon of summer diarrhea and explore its dissipation. We find that water filtration is associated with a 15 percent reduction in diarrheal mortality among children under the age of two during the non-summer months, but does not seem to have had an effect on diarrheal mortality during the summer. In general, we find little evidence to suggest that public health interventions undertaken at the municipal level contributed to the dissipation of summer diarrhea.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eeh.2020.101341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112734PMC
October 2020

Widespread Severe Acute Respiratory Syndrome Coronavirus 2 Transmission Among Attendees at a Large Motorcycle Rally and their Contacts, 30 US Jurisdictions, August-September, 2020.

Clin Infect Dis 2021 07;73(Suppl 1):S106-S109

Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

The 2020 Sturgis motorcycle rally resulted in widespread transmission of severe acute respiratory syndrome coronavirus 2 across the United States. At least 649 coronavirus disease 2019 cases were identified, including secondary and tertiary spread to close contacts. To limit transmission, persons attending events should be vaccinated or wear masks and practice physical distancing if unvaccinated. Persons with a known exposure should be managed according to their coronavirus disease 2019 vaccination or prior infection status and may include quarantine and coronavirus disease 2019 testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciab321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135316PMC
July 2021

Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1.

J Exp Med 2021 07;218(7)

Pediatric Medicine Unit, University Hospital of Besançon, Besançon, France.

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti-IFN-β and another anti-IFN-ε, but none had anti-IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1084/jem.20210554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077172PMC
July 2021

CIGARETTE TAXES AND TEEN MARIJUANA USE.

Natl Tax J 2020 Jun;73(2):475-510

Center for Health Economics and Policy Studies, Department of Economics, San Diego State University, San Diego, CA, USA, and Institute of Labor Economics, Bonn, Germany.

The spillover effect of cigarette taxes on youth marijuana use has been the subject of intense public debate. Opponents of cigarette taxes warn that tax hikes will cause youths to substitute toward marijuana. On the other hand, public health experts often claim that because tobacco is a "gateway" drug, higher cigarette taxes will deter youth marijuana use. Using data from the National and State Youth Risk Behavior Surveys (YRBS) for the period 1991-2017, we explore the relationship between state excise taxes on cigarettes and teen marijuana use. In general, our results fail to support either of the above hypotheses. Rather, we find little evidence to suggest that teen marijuana use is sensitive to changes in the state cigarette tax. This null result holds for the sample period where cigarette taxes are observed to have the largest effect on teen cigarette use and across a number of demographic groups in the data. Finally, we find preliminary evidence that the recent adoption of state e-cigarette taxes is associated with a reduction in youth marijuana use.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.17310/ntj.2020.2.06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059644PMC
June 2020

Gut Microbiome in Progressive Multiple Sclerosis.

Ann Neurol 2021 06 30;89(6):1195-1211. Epub 2021 Apr 30.

Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA.

Objective: This study was undertaken to investigate the gut microbiome in progressive multiple sclerosis (MS) and how it relates to clinical disease.

Methods: We sequenced the microbiota from healthy controls and relapsing-remitting MS (RRMS) and progressive MS patients and correlated the levels of bacteria with clinical features of disease, including Expanded Disability Status Scale (EDSS), quality of life, and brain magnetic resonance imaging lesions/atrophy. We colonized mice with MS-derived Akkermansia and induced experimental autoimmune encephalomyelitis (EAE).

Results: Microbiota β-diversity differed between MS patients and controls but did not differ between RRMS and progressive MS or differ based on disease-modifying therapies. Disease status had the greatest effect on the microbiome β-diversity, followed by body mass index, race, and sex. In both progressive MS and RRMS, we found increased Clostridium bolteae, Ruthenibacterium lactatiformans, and Akkermansia and decreased Blautia wexlerae, Dorea formicigenerans, and Erysipelotrichaceae CCMM. Unique to progressive MS, we found elevated Enterobacteriaceae and Clostridium g24 FCEY and decreased Blautia and Agathobaculum. Several Clostridium species were associated with higher EDSS and fatigue scores. Contrary to the view that elevated Akkermansia in MS has a detrimental role, we found that Akkermansia was linked to lower disability, suggesting a beneficial role. Consistent with this, we found that Akkermansia isolated from MS patients ameliorated EAE, which was linked to a reduction in RORγt+ and IL-17-producing γδ T cells.

Interpretation: Whereas some microbiota alterations are shared in relapsing and progressive MS, we identified unique bacteria associated with progressive MS and clinical measures of disease. Furthermore, elevated Akkermansia in MS may be a compensatory beneficial response in the MS microbiome. ANN NEUROL 2021;89:1195-1211.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.26084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132291PMC
June 2021

To Be or Not to Be a CaMKII Inhibitor?

Authors:
Mark E Anderson

JAMA Cardiol 2021 Jul;6(7):769-770

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamacardio.2021.0701DOI Listing
July 2021

Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET.

J Biol Chem 2021 Jan-Jun;296:100641. Epub 2021 Apr 8.

Janssen Research & Development, Spring House, Pennsylvania, USA. Electronic address:

A bispecific antibody (BsAb) targeting the epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) pathways represents a novel approach to overcome resistance to targeted therapies in patients with non-small cell lung cancer. In this study, we sequentially screened a panel of BsAbs in a combinatorial approach to select the optimal bispecific molecule. The BsAbs were derived from different EGFR and MET parental monoclonal antibodies. Initially, molecules were screened for EGFR and MET binding on tumor cell lines and lack of agonistic activity toward MET. Hits were identified and further screened based on their potential to induce untoward cell proliferation and cross-phosphorylation of EGFR by MET via receptor colocalization in the absence of ligand. After the final step, we selected the EGFR and MET arms for the lead BsAb and added low fucose Fc engineering to generate amivantamab (JNJ-61186372). The crystal structure of the anti-MET Fab of amivantamab bound to MET was solved, and the interaction between the two molecules in atomic details was elucidated. Amivantamab antagonized the hepatocyte growth factor (HGF)-induced signaling by binding to MET Sema domain and thereby blocking HGF β-chain-Sema engagement. The amivantamab EGFR epitope was mapped to EGFR domain III and residues K443, K465, I467, and S468. Furthermore, amivantamab showed superior antitumor activity over small molecule EGFR and MET inhibitors in the HCC827-HGF in vivo model. Based on its unique mode of action, amivantamab may provide benefit to patients with malignancies associated with aberrant EGFR and MET signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jbc.2021.100641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113745PMC
April 2021

Longitudinal single-cell epitope and RNA-sequencing reveals the immunological impact of type 1 interferon autoantibodies in critical COVID-19.

bioRxiv 2021 Mar 10. Epub 2021 Mar 10.

Type I interferon (IFN-I) neutralizing autoantibodies have been found in some critical COVID-19 patients; however, their prevalence and longitudinal dynamics across the disease severity scale, and functional effects on circulating leukocytes remain unknown. Here, in 284 COVID-19 patients, we found IFN-I autoantibodies in 19% of critical, 6% of severe and none of the moderate cases. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 COVID-19 patients, 15 non-COVID-19 patients and 11 non-hospitalized healthy controls, revealed a lack of IFN-I stimulated gene (ISG-I) response in myeloid cells from critical cases, including those producing anti-IFN-I autoantibodies. Moreover, surface protein analysis showed an inverse correlation of the inhibitory receptor LAIR-1 with ISG-I expression response early in the disease course. This aberrant ISG-I response in critical patients with and without IFN-I autoantibodies, supports a unifying model for disease pathogenesis involving ISG-I suppression via convergent mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2021.03.09.434529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987018PMC
March 2021

Travel from the United Kingdom to the United States by a Symptomatic Patient Infected with the SARS-CoV-2 B.1.1.7 Variant - Texas, January 2021.

MMWR Morb Mortal Wkly Rep 2021 Mar 12;70(10):348-349. Epub 2021 Mar 12.

In December 2020, the B.1.1.7 genetic variant of SARS-CoV-2, the virus that causes COVID-19, was first reported after emergence and rapid circulation in the United Kingdom (1). Evidence suggests that the B.1.1.7 variant is more efficiently transmitted than are other SARS-CoV-2 variants, and widespread circulation could thereby increase SARS-CoV-2 infection and hospitalization rates (1,2). The first reported SARS-CoV-2 B.1.1.7 variant case in the United States was confirmed by sequencing in Colorado on December 29, 2020.* This report describes a person who traveled from the United Kingdom to the United States after experiencing COVID-19-compatible symptoms and was eventually confirmed to be infected with the B.1.1.7 variant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15585/mmwr.mm7010e2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951816PMC
March 2021

Pathogenesis of Gram-Negative Bacteremia.

Clin Microbiol Rev 2021 06 10;34(2). Epub 2021 Mar 10.

Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA

Gram-negative bacteremia is a devastating public health threat, with high mortality in vulnerable populations and significant costs to the global economy. Concerningly, rates of both Gram-negative bacteremia and antimicrobial resistance in the causative species are increasing. Gram-negative bacteremia develops in three phases. First, bacteria invade or colonize initial sites of infection. Second, bacteria overcome host barriers, such as immune responses, and disseminate from initial body sites to the bloodstream. Third, bacteria adapt to survive in the blood and blood-filtering organs. To develop new therapies, it is critical to define species-specific and multispecies fitness factors required for bacteremia in model systems that are relevant to human infection. A small subset of species is responsible for the majority of Gram-negative bacteremia cases, including , , , and The few bacteremia fitness factors identified in these prominent Gram-negative species demonstrate shared and unique pathogenic mechanisms at each phase of bacteremia progression. Capsule production, adhesins, and metabolic flexibility are common mediators, whereas only some species utilize toxins. This review provides an overview of Gram-negative bacteremia, compares animal models for bacteremia, and discusses prevalent Gram-negative bacteremia species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/CMR.00234-20DOI Listing
June 2021