Publications by authors named "John L Johnson"

99 Publications

Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis.

N Engl J Med 2021 05;384(18):1705-1718

From the Medical University of South Carolina, Charleston (S.E.D.); the UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco (P.N., P.P.J.P., R.M.S.); the Vietnam National Tuberculosis Program-University of California, San Francisco Research Collaboration Unit (P.N., P.P.J.P., H.T.T.P., N.V.N., T.H.P., R.M.S.) and the National Lung Hospital (N.V.N., T.H.P.) - both in Hanoi; the Centers for Disease Control and Prevention, Atlanta (E.V.K., K.B., S.V.G., A.E.P., N.A.S., E.S., A.V.); the University of Texas Health Science Center at San Antonio and the South Texas Veterans Health Care System, San Antonio (M.E., M.W.); the University of Zimbabwe College of Health Sciences, Harare (J.H., W.S.); Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland (J.L.J.); the Uganda-Case Western Reserve University Research Collaboration, Kampala (J.L.J., G.M.); TASK (M.L.), the University of Cape Town Lung Institute (K.N.), and the South African Tuberculosis Vaccine Initiative (J.S.), Cape Town, the Perinatal HIV Research Unit, University of the Witwatersrand (N.A.M., Z.W.), and the Wits Health Consortium (I.S.), Johannesburg - all in South Africa; Johns Hopkins University School of Medicine, Baltimore (K.E.D., N.A.M., R.E.C.), and the U.S. Public Health Service Commissioned Corps, Rockville (A.E.P.) - both in Maryland; the Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (GHESKIO), Port-au-Prince (S.N., S.P.); and the University of Nebraska Medical Center, Omaha (S.S.).

Background: Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis.

Methods: In an open-label, phase 3, randomized, controlled trial involving persons with newly diagnosed pulmonary tuberculosis from 13 countries, we compared two 4-month rifapentine-based regimens with a standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (control) using a noninferiority margin of 6.6 percentage points. In one 4-month regimen, rifampin was replaced with rifapentine; in the other, rifampin was replaced with rifapentine and ethambutol with moxifloxacin. The primary efficacy outcome was survival free of tuberculosis at 12 months.

Results: Among 2516 participants who had undergone randomization, 2343 had a culture positive for that was not resistant to isoniazid, rifampin, or fluoroquinolones (microbiologically eligible population; 768 in the control group, 791 in the rifapentine-moxifloxacin group, and 784 in the rifapentine group), of whom 194 were coinfected with human immunodeficiency virus and 1703 had cavitation on chest radiography. A total of 2234 participants could be assessed for the primary outcome (assessable population; 726 in the control group, 756 in the rifapentine-moxifloxacin group, and 752 in the rifapentine group). Rifapentine with moxifloxacin was noninferior to the control in the microbiologically eligible population (15.5% vs. 14.6% had an unfavorable outcome; difference, 1.0 percentage point; 95% confidence interval [CI], -2.6 to 4.5) and in the assessable population (11.6% vs. 9.6%; difference, 2.0 percentage points; 95% CI, -1.1 to 5.1). Noninferiority was shown in the secondary and sensitivity analyses. Rifapentine without moxifloxacin was not shown to be noninferior to the control in either population (17.7% vs. 14.6% with an unfavorable outcome in the microbiologically eligible population; difference, 3.0 percentage points [95% CI, -0.6 to 6.6]; and 14.2% vs. 9.6% in the assessable population; difference, 4.4 percentage points [95% CI, 1.2 to 7.7]). Adverse events of grade 3 or higher occurred during the on-treatment period in 19.3% of participants in the control group, 18.8% in the rifapentine-moxifloxacin group, and 14.3% in the rifapentine group.

Conclusions: The efficacy of a 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-month regimen in the treatment of tuberculosis. (Funded by the Centers for Disease Control and Prevention and others; Study 31/A5349 ClinicalTrials.gov number, NCT02410772.).
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http://dx.doi.org/10.1056/NEJMoa2033400DOI Listing
May 2021

Immune cells in bronchoalveolar lavage fluid of Ugandan adults who resist versus those who develop latent Mycobacterium tuberculosis infection.

PLoS One 2021 9;16(4):e0249477. Epub 2021 Apr 9.

Tuberculosis Research Unit and Division of Infectious Diseases, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, Ohio, United States of America.

Background: The search for immune correlates of protection against Mycobacterium tuberculosis (MTB) infection in humans is limited by the focus on peripheral blood measures. Bronchoalveolar lavage (BAL) can safely be done and provides insight into cellular function in the lung where infection is first established. In this study, blood and lung samples were assayed to determine if heavily MTB exposed persons who resist development of latent MTB infection (RSTR) vs those who develop latent MTB infection (LTBI), differ in the make-up of resident BAL innate and adaptive immune cells.

Methods: Bronchoscopy was performed on 21 healthy long-term Ugandan RSTR and 25 LTBI participants. Immune cell distributions in BAL and peripheral blood were compared by differential cell counting and flow cytometry.

Results: The bronchoscopy procedure was well tolerated with few adverse reactions. Differential macrophage and lymphocyte frequencies in BAL differed between RSTR and LTBI. When corrected for age, this difference lost statistical significance. BAL CD4+ and CD8+ T cells were almost entirely composed of effector memory T cells in contrast to PBMC, and did not differ between RSTR and LTBI. BAL NKT, γδ T cells and NK cells also did not differ between RTSR and LTBI participants. There was a marginally significant increase (p = 0.034) in CD8 T effector memory cells re-expressing CD45RA (TEMRA) in PBMC of LTBI vs RSTR participants.

Conclusion: This observational case-control study comparing unstimulated BAL from RSTR vs LTBI, did not find evidence of large differences in the distribution of baseline BAL immune cells. PBMC TEMRA cell percentage was higher in LTBI relative to RSTR suggesting a role in the maintenance of latent MTB infection. Functional immune studies are required to determine if and how RSTR and LTBI BAL immune cells differ in response to MTB.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249477PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034721PMC
April 2021

Decreased plasma rifapentine concentrations associated with AADAC single nucleotide polymorphism in adults with tuberculosis.

J Antimicrob Chemother 2021 Feb;76(3):582-586

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

Background: Rifapentine exposure is associated with bactericidal activity against Mycobacterium tuberculosis, but high interindividual variation in plasma concentrations is encountered.

Objectives: To investigate a genomic association with interindividual variation of rifapentine exposure, SNPs of six human genes involving rifamycin metabolism (AADAC, CES2), drug transport (SLCO1B1, SLCO1B3) and gene regulation (HNF4A, PXR) were evaluated.

Methods: We characterized these genes in 173 adult participants in treatment trials of the Tuberculosis Trials Consortium. Participants were stratified by self-identified race (black or non-black), and rifapentine AUC from 0 to 24 h (AUC0-24) was adjusted by analysis of covariance for SNPs, rifapentine dose, sex, food and HIV coinfection. This study was registered at ClinicalTrials.gov under identifier NCT01043575.

Results: The effect on rifapentine least squares mean AUC0-24 in black participants overall decreased by -10.2% for AADAC rs1803155 G versus A allele (Wald test: P = 0.03; false discovery rate, 0.10). Black participants with one G allele in AADAC rs1803155 were three times as likely to have below target bactericidal rifapentine exposure than black participants with the A allele (OR, 2.97; 95% CI: 1.16, 7.58). With two G alleles, the OR was greater. In non-black participants, AADAC rs1803155 SNP was not associated with rifapentine exposure. In both black and non-black participants, other evaluated genes were not associated with rifapentine exposure (P > 0.05; false discovery rate > 0.10).

Conclusions: Rifapentine exposure in black participants varied with AADAC rs1803155 genotype and the G allele was more likely to be associated with below bactericidal target rifapentine exposure. Further pharmacogenomic study is needed to characterize the association of the AADAC rs1803155 with inadequate rifapentine exposure in different patient groups.
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http://dx.doi.org/10.1093/jac/dkaa490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879139PMC
February 2021

Level of education and preferred language of informed consent for clinical research in a multi-lingual community.

Afr Health Sci 2020 Jun;20(2):955-959

Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda.

Background: Low education levels and language barriers present challenges in obtaining informed consent for clinical research.

Objective: To describe and correlate the association between the level of education and the participant's preferred language of consent.

Design: Descriptive-analytical cross-sectional study.

Participants: Adults being consented for participation in tuberculosis(TB) research studies in an East African community with varying levels of education.

Procedures: We analyzed data on demographic and educational characteristics collected from adults being consented for participation in TB studies .Only participants who could understand and speak Luganda (the main local language) or English (the official language of Uganda) were included in this analysis.

Results: A total of 523 participants were consented between April 2015 and December 2017 and included in this analysis; 250 below Senior four (< 11yrs of education), 114 senior four (at 11yrs of education),73 senior five-senior six (12-13yrs of education) and 86 beyond senior six (> 13yrs of education). We noted that the preference for English rises with the rising levels of education and peaked at beyond senior six (83%Vs17%,OR=49,95%CI:22.8-106.3,p<0.001).Participants below senior four preferred Luganda Vs senior four and above(OR=16.9,95%CI:9.9-28.8,p<0.001).

Conclusion: Rising education levels of participants were associated with preference for English language usage during initial consent for clinical research studies.
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http://dx.doi.org/10.4314/ahs.v20i2.51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609127PMC
June 2020

Fluorescence Imaging of the Ureter in Minimally Invasive Pelvic Surgery.

J Minim Invasive Gynecol 2021 02 29;28(2):332-341.e14. Epub 2020 Jun 29.

Division of Gynecologic Oncology, University of Alabama, Birmingham, Alabama (Drs. Kim, Johnson, Leath III, Huh, and Ms. Elliott); Department of Obstetrics and Gynecology, University of Tennessee Medical Center Knoxville, Graduate School of Medicine, Knoxville, Tennessee (Dr. Boone); Clinical Research and Development, LI-COR, Inc., Lincoln, Nebraska (Ms. Kovar).

Study Objective: Determine near-optimal dose, safety, and efficacy of nerindocianine in pelvic ureter detection with near-infrared fluorescence imaging in women undergoing minimally invasive pelvic surgery with 3 Food and Drug Administration-cleared imaging systems.

Design: Open label, phase 1/2a study.

Setting: University of Alabama at Birmingham.

Patients: Forty-one female subjects undergoing minimally invasive gynecologic surgery.

Interventions: Subjects received a single dose of nerindocianine sodium, starting at 0.06-mg/kg body weight and increased/decreased until the near-optimal dose was determined (part A). Examine the degree of concordance between endoscopic and robotic devices (part B).

Measurements And Main Results: In part A, composite scores were collected every 10 minutes for 30 minutes and then every 15 minutes through 90 minutes using a scale measuring the anatomy/laterality of ureter visualization. In part B (paired imaging system efficacy), 2 cohorts of 8 subjects each received the near-optimal dose. Composite scores for visualization of the ureter were collected at 10 and 30 minutes postinfusion with the Firefly Imaging System and either the PINPOINT or 1588 AIM endoscope. Composite scores were compared to examine the degree of concordance between devices. Part A comprised 25 total subjects enrolled in dosing groups 1, 2, and 3 (0.06-, 0.12-, and 0.045-mg/kg, respectively). Median time to first ureter visualization was 10 minutes (all groups). The nerindocianine 0.06-mg/kg and 0.12-mg/kg groups had longer length of time of visualization than the 0.045-mg/kg group, resulting in the selection of 0.06 mg/kg as the near-optimal dose. Part B enrolled 16 total subjects in 2 groups dosed at 0.06 mg/kg. Efficacy analysis showed no statistically significant difference in composite scores with Firefly versus PINPOINT or 1588 AIM.

Conclusion: Nerindocianine was well tolerated with visualization of the ureter demonstrated in 88.9% of the subjects through 90 minutes postdosing. No meaningful visualization differences were observed among the Food and Drug Administration-cleared surgical imaging systems used.
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http://dx.doi.org/10.1016/j.jmig.2020.06.022DOI Listing
February 2021

The Transcription Factor T-bet Resolves Memory B Cell Subsets with Distinct Tissue Distributions and Antibody Specificities in Mice and Humans.

Immunity 2020 05 29;52(5):842-855.e6. Epub 2020 Apr 29.

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

B cell subsets expressing the transcription factor T-bet are associated with humoral immune responses and autoimmunity. Here, we examined the anatomic distribution, clonal relationships, and functional properties of T-bet and T-bet memory B cells (MBCs) in the context of the influenza-specific immune response. In mice, both T-bet and T-bet hemagglutinin (HA)-specific B cells arose in germinal centers, acquired memory B cell markers, and persisted indefinitely. Lineage tracing and IgH repertoire analyses revealed minimal interconversion between T-bet and T-bet MBCs, and parabionts showed differential tissue residency and recirculation properties. T-bet MBCs could be subdivided into recirculating T-bet MBCs and spleen-resident T-bet MBCs. Human MBCs displayed similar features. Conditional gene deletion studies revealed that T-bet expression in B cells was required for nearly all HA stalk-specific IgG2c antibodies and for durable neutralizing titers to influenza. Thus, T-bet expression distinguishes MBC subsets that have profoundly different homing, residency, and functional properties, and mediate distinct aspects of humoral immune memory.
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http://dx.doi.org/10.1016/j.immuni.2020.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242168PMC
May 2020

High-dose rifapentine with or without moxifloxacin for shortening treatment of pulmonary tuberculosis: Study protocol for TBTC study 31/ACTG A5349 phase 3 clinical trial.

Contemp Clin Trials 2020 03 22;90:105938. Epub 2020 Jan 22.

Audie L. Murphy Veterans Affairs Medical Center / University of Texas Health Science Center, San Antonio, TX, USA.

Introduction: Phase 2 clinical trials of tuberculosis treatment have shown that once-daily regimens in which rifampin is replaced by high dose rifapentine have potent antimicrobial activity that may be sufficient to shorten overall treatment duration. Herein we describe the design of an ongoing phase 3 clinical trial testing the hypothesis that once-daily regimens containing high dose rifapentine in combination with other anti-tuberculosis drugs administered for four months can achieve cure rates not worse than the conventional six-month treatment regimen.

Methods/design: S31/A5349 is a multicenter randomized controlled phase 3 non-inferiority trial that compares two four-month regimens with the standard six-month regimen for treating drug-susceptible pulmonary tuberculosis in HIV-negative and HIV-positive patients. Both of the four-month regimens contain high-dose rifapentine instead of rifampin, with ethambutol replaced by moxifloxacin in one regimen. All drugs are administered seven days per week, and under direct observation at least five days per week. The primary outcome is tuberculosis disease-free survival at twelve months after study treatment assignment. A total of 2500 participants will be randomized; this gives 90% power to show non-inferiority with a 6.6% margin of non-inferiority.

Discussion: This phase 3 trial formally tests the hypothesis that augmentation of rifamycin exposures can shorten tuberculosis treatment to four months. Trial design and standardized implementation optimize the likelihood of obtaining valid results. Results of this trial may have important implications for clinical management of tuberculosis at both individual and programmatic levels.

Trial Registration: NCT02410772. Registered 8 April 2015,https://www.clinicaltrials.gov/ct2/show/NCT02410772?term=02410772&rank=1.
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http://dx.doi.org/10.1016/j.cct.2020.105938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307310PMC
March 2020

Predictors of recurrent TB in sputum smear and culture positive adults: a prospective cohort study.

Afr Health Sci 2019 Jun;19(2):2091-2099

Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda.

Objective: To explore simple inexpensive non-culture based predictors of recurrent pulmonary tuberculosis (PTB).

Setting And Study Population: HIV-infected and uninfected adults with the first episode of smear positive, culture-confirmed pulmonary tuberculosis in a high tuberculosis burden country.

Design: A nested prospective cohort study of participants with pulmonary tuberculosis (PTB) presenting to a hospital out-patient clinic.

Results: A total of 630 TB culture confirmed participants were followed up for eighteen months of which 57 (9%) developed recurrent recurrent TB. On univariate analysis,4.7% low grade(1+) pre-treatment sputum smear participants developed recurrent tuberculosis Vs 8.8% with high grade(3+) smears (OR=0.31,95%CI: 0.10-0.93, p=0.037).On multivariate analysis: participants with extensive fibro-cavitation had a high risk of recurrent TB Vs minimal end of treatment fibro-cavitation (18%Vs12%, OR=2.3,95%CI:1.09-4.68, p=0.03). Weight gain with HIV infection was assosciated with a high risk of recurrent TB Vs weight gain with no HIV infection(18%Vs 6%, OR=6.8,95%CI:165-27.83, p=0.008) where as weight gain with a low pre-treatment high bacillary burden was assosciated with a low risk of recurrent TB Vs weight gain with a high pre-treatmentbacillary burden(6.5%Vs7.9%, OR=0.2,95%CI:0.05-0.79, p=0.02).

Conclusion: Extensive end of treatment pulmonary fibro-cavitation, high pre-treatment bacillary burden with no weight gain and HIV infection could be reliable predictors of recurrent tuberculosis.
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http://dx.doi.org/10.4314/ahs.v19i2.33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794518PMC
June 2019

MR1-Independent Activation of Human Mucosal-Associated Invariant T Cells by Mycobacteria.

J Immunol 2019 12 14;203(11):2917-2927. Epub 2019 Oct 14.

South African Tuberculosis Vaccine Initiative, University of Cape Town, Cape Town 7925, South Africa.

Tuberculosis (TB) is the leading cause of mortality from a single infectious agent, Relevant immune targets of the partially efficacious TB vaccine bacille Calmette-Guérin (BCG) remain poorly defined. Mucosal-associated invariant T (MAIT) cells are MHC-related protein 1 (MR1)-restricted T cells, which are reactive against , and underexplored as potential TB vaccine targets. We sought to determine whether BCG vaccination activated mycobacteria-specific MAIT cell responses in humans. We analyzed whole blood samples from infected South African adults who were revaccinated with BCG after a six-month course of isoniazid preventative therapy. In vitro BCG stimulation potently induced IFN-γ expression by phenotypic (CD8CD26CD161) MAIT cells, which constituted the majority (75%) of BCG-reactive IFN-γ-producing CD8 T cells. BCG revaccination transiently expanded peripheral blood frequencies of BCG-reactive IFN-γ MAIT cells, which returned to baseline frequencies a year following vaccination. In another cohort of healthy adults who received BCG at birth, 53% of mycobacteria-reactive-activated CD8 T cells expressed CDR3α TCRs, previously reported as MAIT TCRs, expressing the canonical TRAV1-2-TRAJ33 MAIT TCRα rearrangement. CD26 and CD161 coexpression correlated with TRAV1-2CD161 phenotype more accurately in CD8 than CD4CD8 MAIT cells. Interestingly, BCG-induced IFN-γ expression by MAIT cells in vitro was mediated by the innate cytokines IL-12 and IL-18 more than MR1-induced TCR signaling, suggesting TCR-independent activation. Collectively, the data suggest that activation of blood MAIT cells by innate inflammatory cytokines is a major mechanism of responsiveness to vaccination with whole cell vaccines against TB or in vitro stimulation with mycobacteria ( NCT01119521).
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http://dx.doi.org/10.4049/jimmunol.1900674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859375PMC
December 2019

First tarsometatarsal fusion using saw preparation vs. standard preparation of the joint: A cadaver study.

Foot Ankle Surg 2020 Aug 13;26(6):703-707. Epub 2019 Sep 13.

Department of Orthopaedic Surgery, University of Alabama, 1313 13th Street South, Birmingham, AL 35205, USA. Electronic address:

Background: First tarsometatarsal (TMT) joint fusion is effective for treatment of arthritis and some first ray deformities. To prepare the articular surfaces, cartilage should be carefully but completely denuded. Inadequate preparation may result in non-union, while excessive preparation may cause ray shortening and consequential transfer metatarsalgia. Preparation can be performed with an osteotome or a saw. The purpose of this study was to investigate whether utilization of an osteotome or saw would minimize shortening of the first ray in TMT arthrodesis.

Methods: Ten fresh-frozen cadaver specimens were randomly assigned to undergo joint preparation using either an osteotome (n=5) or saw (n=5). Sample size was determined by cadaver availability. Fusion was performed using a cross-screw construct through the dorsal aspect of the proximal phalanx and the medial cuneiform. Pre- and post-operative X-rays were taken with a radiopaque ruler in the field, and changes in length in the first metatarsal and first cuneiform were compared between osteotome and sawblade groups.

Results: The average change in metatarsal length was significantly smaller in the osteotome group (1.6mm) as compared to the saw group (4.4mm) (p=0.031). The average percent change in metatarsal length was also significantly smaller in the osteotome group (3.0%) compared to the saw group (8.4%) (p=0.025). There was no significant difference between the two groups with respect to change in cuneiform length. The osteotome group demonstrated a significantly smaller average measured change (3.0mm vs. 6.9mm, p=0.001) and percent change (4.1% vs. 9.3%, p<0.001) in total length (cuneiform plus metatarsal) in comparison to the saw group.

Conclusions: In first TMT fusion, joint preparation with an osteotome may prevent over-shortening of the first ray in comparison to preparation with a saw.
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http://dx.doi.org/10.1016/j.fas.2019.08.016DOI Listing
August 2020

Molecular pattern recognition in peripheral B cell tolerance: lessons from age-associated B cells.

Curr Opin Immunol 2019 12 23;61:33-38. Epub 2019 Aug 23.

Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, United States. Electronic address:

Although central tolerance mechanisms purge self-reactive B cells during development based on BCR signal strength, mechanisms that block the differentiation of autoreactive effector and memory B cells from mature pools remain poorly understood. Prior observations implicate nucleic acid sensing TLRs in autoimmunity, and more recent findings show that TLR9 is also involved in maintaining peripheral tolerance. Studies of the immunological changes that occur during aging revealed a subset of B cells denoted Age-associated B cells which expands in settings of aging and in autoimmunity. Further studies demonstrated that TLR9 signals poise activated B cells to adopt an Age-associated B cell phenotype, but BCR-delivered TLR9 signals cause programmed cell death that, if circumvented by costimulation, allows continued differentiation to the ABC fate. Together, these observations suggest molecular pattern recognition, rather than BCR epitope specificity per se, is a fundamental mediator of tolerogenic outcomes in the peripheral B cell activation.
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http://dx.doi.org/10.1016/j.coi.2019.07.008DOI Listing
December 2019

Distinct serum biosignatures are associated with different tuberculosis treatment outcomes.

Tuberculosis (Edinb) 2019 09 12;118:101859. Epub 2019 Aug 12.

DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address:

Biomarkers for TB treatment response and outcome are needed. This study characterize changes in immune profiles during TB treatment, define biosignatures associated with treatment outcomes, and explore the feasibility of predictive models for relapse. Seventy-two markers were measured by multiplex cytokine array in serum samples from 78 cured, 12 relapsed and 15 failed treatment patients from South Africa before and during therapy for pulmonary TB. Promising biosignatures were evaluated in a second cohort from Uganda/Brazil consisting of 17 relapse and 23 cured patients. Thirty markers changed significantly with different response patterns during TB treatment in cured patients. The serum biosignature distinguished cured from relapse patients and a combination of two clinical (time to positivity in liquid culture and BMI) and four immunological parameters (TNF-β, sIL-6R, IL-12p40 and IP-10) at diagnosis predicted relapse with a 75% sensitivity (95%CI 0.38-1) and 85% specificity (95%CI 0.75-0.93). This biosignature was validated in an independent Uganda/Brazil cohort correctly classifying relapse patients with 83% (95%CI 0.58-1) sensitivity and 61% (95%CI 0.39-0.83) specificity. A characteristic biosignature with value as predictor of TB relapse was identified. The repeatability and robustness of these biomarkers require further validation in well-characterized cohorts.
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http://dx.doi.org/10.1016/j.tube.2019.101859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839616PMC
September 2019

Cell-Intrinsic Wnt4 Influences Conventional Dendritic Cell Fate Determination to Suppress Type 2 Immunity.

J Immunol 2019 07 7;203(2):511-519. Epub 2019 Jun 7.

Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104

Whether conventional dendritic cells (cDC) acquire subset identity under direction of Wnt family glycoproteins is unknown. We demonstrate that Wnt4, a β-catenin-independent Wnt ligand, is produced by both hematopoietic and nonhematopoietic cells and is both necessary and sufficient for preconventional DC1/cDC1 maintenance. Whereas bone marrow cDC precursors undergo phosphoJNK/c-Jun activation upon Wnt4 treatment, loss of cDC Wnt4 in CD11cWnt4 mice impaired differentiation of CD24, Clec9A, CD103 cDC1 compared with CD11c controls. Conversely, single-cell RNA sequencing analysis of bone marrow revealed a 2-fold increase in cDC2 gene signature genes, and flow cytometry demonstrated increased numbers of SIRP-α cDC2 amid lack of Wnt4. Increased cDC2 numbers due to CD11c-restricted Wnt4 deficiency increased IL-5 production, group 2 innate lymphoid cell expansion, and host resistance to the hookworm parasite Collectively, these data uncover a novel and unexpected role for Wnt4 in cDC subset differentiation and type 2 immunity.
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http://dx.doi.org/10.4049/jimmunol.1900363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615948PMC
July 2019

Outcomes of Inpatient Versus Outpatient Elective Foot and Ankle Surgery.

Cureus 2019 Feb 12;11(2):e4058. Epub 2019 Feb 12.

Orthopaedics, University of Alabama School of Medicine, Birmingham, USA.

Background Complications following orthopedic surgeries are undesirable and costly. A potential method to reduce these costs is to perform traditionally inpatient surgical procedures in the outpatient setting. The purpose of this study is to compare outcomes between inpatient and outpatient settings for elective foot and ankle surgeries using the National Surgical Quality Improvement Program (NSQIP) database. Methods Patients with Current Procedural Terminology (CPT) codes specific to orthopedic foot and ankle surgery were identified from the 2011-2015 American College of Surgeons NSQIP database. Demographics, comorbidities, and complications were compared between patients undergoing inpatient and outpatient procedures. Results Patients receiving inpatient surgery were significantly older and more frequently male. Black patients were significantly more likely to undergo inpatient surgery than outpatient surgery while white patients were significantly more likely to undergo outpatient surgery. Outpatients had a significantly higher mean body mass index (BMI) than inpatients. Smokers were at a significantly greater risk of undergoing inpatient surgery than outpatient surgery. Outpatients had significantly longer operative times, were more likely to receive general anesthesia, had a lower American Society of Anesthesiologists (ASA) class, were more likely to be functionally independent, and were less likely to expire postoperatively. Patients who received surgery as an inpatient were significantly more likely to have comorbidities as compared to outpatients. The overall risk of surgical complications was significant between groups with 8.6% in the inpatient group and 2.0% in the outpatient group. The overall risk of medical complications was 16.9% in the inpatient group and 1.7% in the outpatient group. Similar to the surgical complications, inpatients were significantly more likely to sustain each of the individual medical complications except for stroke/CVA and venous thromboembolism. Conclusions Outpatient management is associated with decreased postoperative complications in select patients. Performing more operations in the outpatient setting in select patients may be beneficial for cost reduction and patient satisfaction.
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http://dx.doi.org/10.7759/cureus.4058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464278PMC
February 2019

Limited Sampling Strategies Using Linear Regression and the Bayesian Approach for Therapeutic Drug Monitoring of Moxifloxacin in Tuberculosis Patients.

Antimicrob Agents Chemother 2019 07 24;63(7). Epub 2019 Jun 24.

University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands

Therapeutic drug monitoring (TDM) of moxifloxacin is recommended to improve the response to tuberculosis treatment and reduce acquired drug resistance. Limited sampling strategies (LSSs) are able to reduce the burden of TDM by using a small number of appropriately timed samples to estimate the parameter of interest, the area under the concentration-time curve. This study aimed to develop LSSs for moxifloxacin alone (MFX) and together with rifampin (MFX+RIF) in tuberculosis (TB) patients. Population pharmacokinetic (popPK) models were developed for MFX ( = 77) and MFX+RIF ( = 24). In addition, LSSs using Bayesian approach and multiple linear regression were developed. Jackknife analysis was used for internal validation of the popPK models and multiple linear regression LSSs. Clinically feasible LSSs (one to three samples, 6-h timespan postdose, and 1-h interval) were tested. Moxifloxacin exposure was slightly underestimated in the one-compartment models of MFX (mean -5.1%, standard error [SE] 0.8%) and MFX+RIF (mean -10%, SE 2.5%). The Bayesian LSSs for MFX and MFX+RIF (both 0 and 6 h) slightly underestimated drug exposure (MFX mean -4.8%, SE 1.3%; MFX+RIF mean -5.5%, SE 3.1%). The multiple linear regression LSS for MFX (0 and 4 h) and MFX+RIF (1 and 6 h), showed mean overestimations of 0.2% (SE 1.3%) and 0.9% (SE 2.1%), respectively. LSSs were successfully developed using the Bayesian approach (MFX and MFX+RIF; 0 and 6 h) and multiple linear regression (MFX, 0 and 4 h; MFX+RIF, 1 and 6 h). These LSSs can be implemented in clinical practice to facilitate TDM of moxifloxacin in TB patients.
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http://dx.doi.org/10.1128/AAC.00384-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591620PMC
July 2019

Impact of Diabetes Mellitus on the Presentation and Response to Treatment of Adults With Pulmonary Tuberculosis in Qatar.

Open Forum Infect Dis 2019 Jan 19;6(1):ofy335. Epub 2018 Dec 19.

Division of Infectious Diseases & HIV Medicine, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, Ohio.

Background: Persons with diabetes mellitus (DM) have a 3-fold increased risk of tuberculosis (TB). Atypical radiographic findings and differences in bacteriologic response during anti-TB treatment have been reported in earlier studies; however, the findings have varied. We evaluated the effect of DM on manifestations and response to treatment in adults with pulmonary TB in Qatar.

Methods: The impact of DM on the clinical and radiographic presentations of pulmonary TB and bacteriologic response during anti-TB treatment was evaluated between January 2007 and December 2011, comparing patients with and without DM. This is a retrospective unmatched case-control study conducted at a large national hospital. Cases and controls were randomly selected from patients diagnosed with pulmonary TB over a 5-year period. Sputum culture conversion was assessed after 2 months of anti-TB treatment.

Results: Clinical symptoms were similar between patients with and without DM. Patients with DM had a higher initial sputum acid-fast bacillus (AFB) smear grade and were less likely to have cavitary lesions on initial chest radiographs than patients without DM. Of 134 adults with DM and TB, 71 (53%) remained sputum culture positive after 2 months of anti-TB treatment, compared with 36 (27%) patients without DM.

Conclusions: DM was associated with atypical radiographic findings and delayed sputum culture conversion at 2 months in adults with pulmonary TB in Qatar. Increased health education of patients with DM about symptoms of TB, low thresholds for evaluation for active TB, and close monitoring of bacteriologic response to treatment among patients with TB and DM are warranted.
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http://dx.doi.org/10.1093/ofid/ofy335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324545PMC
January 2019

Elucidation of a Human Urine Metabolite as a Seryl-Leucine Glycopeptide and as a Biomarker of Effective Anti-Tuberculosis Therapy.

ACS Infect Dis 2019 03 10;5(3):353-364. Epub 2019 Jan 10.

Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology , Colorado State University , 200 West Lake Street, 0922 Campus Delivery , Fort Collins , Colorado 80523 , United States.

The evaluation of new tuberculosis (TB) therapies is limited by the paucity of biomarkers to monitor treatment response. Previous work detected an uncharacterized urine metabolite with a molecular mass of 874.3547 Da that showed promise as a biomarker for successful TB treatment. Using mass spectrometry combined with enzymatic digestions, the metabolite was structurally characterized as a seryl-leucine core 1 O-glycosylated peptide (SLC1G) of human origin. Examination of SLC1G in urine revealed a significant abundance increase in individuals with active TB versus their household contacts and healthy controls. Moreover, differential decreases in SLC1G levels were observed by week one in TB patients during successful treatment versus those that failed treatment. The SLC1G levels were also associated with clinical parameters used to measure bacterial burden (GeneXpert) and inflammation (positron emission tomography-computed tomography (PET-CT)). These results demonstrate the importance of metabolite identification and provide strong evidence for applying SLC1G as a biomarker of TB treatment response.
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http://dx.doi.org/10.1021/acsinfecdis.8b00241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412501PMC
March 2019

Publisher Correction: A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis.

Nat Med 2019 Jan;25(1):190

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

The version of this article originally published was not open access. This article should have been open access. The error has been fixed, and the article is now open access.
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http://dx.doi.org/10.1038/s41591-018-0294-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608289PMC
January 2019

A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis.

Nat Med 2018 11 5;24(11):1708-1715. Epub 2018 Nov 5.

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

Tuberculosis kills more people than any other infectious disease. Three pivotal trials testing 4-month regimens failed to meet non-inferiority margins; however, approximately four-fifths of participants were cured. Through a pooled analysis of patient-level data with external validation, we identify populations eligible for 4-month treatment, define phenotypes that are hard to treat and evaluate the impact of adherence and dosing strategy on outcomes. In 3,405 participants included in analyses, baseline smear grade of 3+ relative to <2+, HIV seropositivity and adherence of ≤90% were significant risk factors for unfavorable outcome. Four-month regimens were non-inferior in participants with minimal disease defined by <2+ sputum smear grade or non-cavitary disease. A hard-to-treat phenotype, defined by high smear grades and cavitation, may require durations >6 months to cure all. Regimen duration can be selected in order to improve outcomes, providing a stratified medicine approach as an alternative to the 'one-size-fits-all' treatment currently used worldwide.
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http://dx.doi.org/10.1038/s41591-018-0224-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685538PMC
November 2018

Is interposition arthroplasty a viable option for treatment of moderate to severe hallux rigidus? - A systematic review and meta-analysis.

Foot Ankle Surg 2019 Oct 23;25(5):571-579. Epub 2018 Jul 23.

Department of Orthopedic Surgery, Division of Foot and Ankle surgery, University of Alabama at Birmingham, USA. Electronic address:

Introduction: When conservative therapy for hallux rigidus fails, surgical options such as arthrodesis and interposition arthroplasty can be considered. Although arthrodesis of MTP joint is the gold standard treatment. However patients desiring MTP joint movement may opt for either interposition arthroplasty or implant arthroplasty to avoid the movement restrictions of arthrodesis. The purpose of this systematic review was to investigate clinical outcomes and complications following interposition arthroplasty for moderate to severe hallux rigidus, for patietns who would prefer to maintain range of motion in the MTP joint.

Methods: A systematic search on MEDLINE, EMBASE and Cochrane library database was performed during February 2018. Demographics, surgical techniques, clinical outcomes, radiological outcomes and complications were recorded from each included study. Pooled statistics performed for variables with homogenous data across the studies. A linear regression model used to compare the clinical outcomes between autogenous vs allogenous material interposition arthroplasty.

Results: Fifteen articles were included in the systematic review. Mean AOFAS scores improved from preoperative 41.35 to postoperative 83.17. Mean pain, function, and alignment score improved from preoperative values of 14.9, 24.9, and 10 to postoperative values of 33.3, 35.8, and 14.5. Mean dorsiflexion increased from 21.27° (5-30) to 42.03° (25-71). Mean ROM improved from 21.06° to 46.43°. Joint space increased from 0.8mm to 2.5mm. The most common postoperative complications included metatarsalgia (13.9%), loss of ground contact (9.7%), osteonecrosis (5.4%), great toe weakness (4.8%), hypoesthesia (4.2%), decreased push off power (4.2%), and callous formation (4.2%).

Conclusion: Interposition arthroplasty is an effective treatment option with acceptable clinical outcomes in patients with moderate-severe hallux rigidus who prefer to maintain range of motion and accept the risk of future complications.

Level Of Evidence: IV.
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http://dx.doi.org/10.1016/j.fas.2018.07.006DOI Listing
October 2019

The surgical anatomy of the dorsal scapular nerve: a triple-tendon transfer perspective.

J Shoulder Elbow Surg 2019 Jan 11;28(1):137-142. Epub 2018 Oct 11.

Department of Orthopedic Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.

Background: Iatrogenic or traumatic injury to the spinal accessory nerve is a rare but debilitating injury. An effective treatment, known as the Eden-Lange modification triple-tendon transfer procedure, involves the transfer of the rhomboid major (RM), rhomboid minor (Rm), and levator scapulae (LS). Careful detachment of their insertions is necessary to avoid injury of the dorsal scapular nerve (DSN). This study evaluated the surgical anatomy and safety of the DSN relative to this procedure.

Methods: The study used 12 cadavers (22 shoulders). The RM, Rm, and LS were detached from their insertions, and the DSN was dissected. Measurements were taken to evaluate the anatomy of each relative to the triple-tendon transfer procedure. Additional measurements were taken to identify "danger zones" for DSN injury, regarding detachment of RM, Rm, and LS from their respective insertions.

Results: Measurements of the 22 shoulders included in the study showed wide variation in anatomy. The minimum distance between the scapula and the DSN at the vertebral scapular border was 0.7 cm, suggesting that care and precision are needed to perform this technique. The region where the DSN crosses the superior border of the Rm was shown to be the greatest "danger zone" of this technique, with a mean distance to the scapula of 1.61 ± 0.53 cm CONCLUSIONS: This study provides insight into the surgical anatomy of the DSN relative to a rare but successful procedure used to treat trapezius paralysis. The results of this study can inform the surgeon regarding potential anatomic considerations when performing the triple-tendon transfer.
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http://dx.doi.org/10.1016/j.jse.2018.07.005DOI Listing
January 2019

Risk Factors for Readmission Following Revision Total Hip Arthroplasty in Patients Undergoing Surgery for Noninfective Causes.

Cureus 2018 Jul 6;10(7):e2934. Epub 2018 Jul 6.

Orthopaedic Surgery, University of Alabama at Birmingham, Birmingham, USA.

Introduction Readmission following revision orthopedic surgery imposes tremendous costs due to the increased length of stay, procedure complexity, and revision surgery. Following revision total hip arthroplasty, as many as one in five patients are readmitted postoperatively. Readmissions cost the federal government $17.4 billion annually. The purpose of this study was to identify risk factors for unplanned readmission following revision total hip arthroplasty. Methods This was a retrospective case series review of randomized revision total hip arthroplasties (THA) patients between 2008 and 2018. Exclusions were as follows: outside hospital revisions, staged revisions, revisions for infection, and bilateral revisions. Data were collected by manual chart review. Readmissions were tracked from discharge until the final follow-up. Results A total of 61 patients and 85 revision THAs were analyzed. Nineteen patients (31.1%) were readmitted; 31.6% of the readmitted patients had a coronary artery disease compared to 6.5% of non-readmitted patients. Readmission was also associated with obesity, former smokers, and hypertension. Also, the mean duration of follow-up was 26.5 months for readmitted patients as compared to 8.96 for non-readmitted patients. Conclusion Obesity, former tobacco use, younger age, coronary artery disease (CAD), and hypertension were associated with readmission. The medical optimization of patients with these risk factors prior to surgery could significantly lower costs relative to revision THA.
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http://dx.doi.org/10.7759/cureus.2934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128606PMC
July 2018

A Cosine Similarity-Based Method to Infer Variability of Chromatin Accessibility at the Single-Cell Level.

Front Genet 2018 15;9:319. Epub 2018 Aug 15.

Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.

Cellular identity between generations of developing cells is propagated through the epigenome particularly via the accessible parts of the chromatin. It is now possible to measure chromatin accessibility at single-cell resolution using single-cell assay for transposase accessible chromatin (scATAC-seq), which can reveal the regulatory variation behind the phenotypic variation. However, single-cell chromatin accessibility data are sparse, binary, and high dimensional, leading to unique computational challenges. To overcome these difficulties, we developed PRISM, a computational workflow that quantifies cell-to-cell chromatin accessibility variation while controlling for technical biases. PRISM is a novel multidimensional scaling-based method using angular cosine distance metrics coupled with distance from the spatial centroid. PRISM takes differences in accessibility at each genomic region between single cells into account. Using data generated in our lab and publicly available, we showed that PRISM outperforms an existing algorithm, which relies on the aggregate of signal across a set of genomic regions. PRISM showed robustness to noise in cells with low coverage for measuring chromatin accessibility. Our approach revealed the previously undetected accessibility variation where accessible sites differ between cells but the total number of accessible sites is constant. We also showed that PRISM, but not an existing algorithm, can find suppressed heterogeneity of accessibility at CTCF binding sites. Our updated approach uncovers new biological results with profound implications on the cellular heterogeneity of chromatin architecture.
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http://dx.doi.org/10.3389/fgene.2018.00319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103536PMC
August 2018

Bacterial Factors That Predict Relapse after Tuberculosis Therapy.

N Engl J Med 2018 Aug;379(9):823-833

From the Department of Medicine, Rutgers-New Jersey Medical School (R. Colangeli, H.J., U.D.C.V., S.C., A.G., D.A.), and the Department of Biostatistics, Rutgers School of Public Health (S.K., R. Connell), Newark; the Center for Infectious Disease Research, Seattle (S.M., D.R.S.); the Centers for Disease Control and Prevention, Atlanta (E.E.S., L.D., W.R.M.K.); Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda (A.O.); Nucleo de Doencas Infecciosas, Centro de Ciencias da Saude, Universidade Federal do Espirito Santo, Vitoria, Brazil (R.D.); and the Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland (W.H.B., J.L.J.).

Background: Approximately 5% of patients with drug-susceptible tuberculosis have a relapse after 6 months of first-line therapy, as do approximately 20% of patients after 4 months of short-course therapy. We postulated that by analyzing pretreatment isolates of Mycobacterium tuberculosis obtained from patients who subsequently had a relapse or were cured, we could determine any correlations between the minimum inhibitory concentration (MIC) of a drug below the standard resistance breakpoint and the relapse risk after treatment.

Methods: Using data from the Tuberculosis Trials Consortium Study 22 (development cohort), we assessed relapse and cure isolates to determine the MIC values of isoniazid and rifampin that were below the standard resistance breakpoint (0.1 μg per milliliter for isoniazid and 1.0 μg per milliliter for rifampin). We combined this analysis with clinical, radiologic, and laboratory data to generate predictive relapse models, which we validated by analyzing data from the DMID 01-009 study (validation cohort).

Results: In the development cohort, the mean (±SD) MIC of isoniazid below the breakpoint was 0.0334±0.0085 μg per milliliter in the relapse group and 0.0286±0.0092 μg per milliliter in the cure group, which represented a higher value in the relapse group by a factor of 1.17 (P=0.02). The corresponding MIC values of rifampin were 0.0695±0.0276 and 0.0453±0.0223 μg per milliliter, respectively, which represented a higher value in the relapse group by a factor of 1.53 (P<0.001). Higher MIC values remained associated with relapse in a multivariable analysis that included other significant between-group differences. In an analysis of receiver-operating-characteristic curves of relapse based on these MIC values, the area under the curve (AUC) was 0.779. In the development cohort, the AUC in a multivariable model that included MIC values was 0.875. In the validation cohort, the MIC values either alone or combined with other patient characteristics were also predictive of relapse, with AUC values of 0.964 and 0.929, respectively. The use of a model score for the MIC values of isoniazid and rifampin to achieve 75.0% sensitivity in cross-validation analysis predicted relapse with a specificity of 76.5% in the development cohort and a sensitivity of 70.0% and a specificity of 100% in the validation cohort.

Conclusions: In pretreatment isolates of M. tuberculosis with decrements of MIC values of isoniazid or rifampin below standard resistance breakpoints, higher MIC values were associated with a greater risk of relapse than lower MIC values. (Funded by the National Institute of Allergy and Infectious Diseases.).
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http://dx.doi.org/10.1056/NEJMoa1715849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317071PMC
August 2018

Morton's Neuroma Excision: What Are We Really Doing? Which Retractor Is Superior?

Foot Ankle Spec 2019 Jun 15;12(3):272-277. Epub 2018 Aug 15.

University of Alabama at Birmingham School of Medicine, Birmingham, Alabama.

Background: When using a dorsal approach for Morton's neuroma excision, the most common complication is recurrent Morton's neuroma. The present cadaveric study demonstrates how far proximally the nerve is resected during a dorsal approach and examines both the laminar spreader and Gelpiretractor to determine which instrument facilitates maximal proximal resection of the nerve.

Methods: This study involved 12 fresh-frozen cadaver specimens, each of which underwent a dorsal approach to the interdigital nerve with proximal resection. Either a laminar spreader or a Gelpi retractor was used to improve visualization of the intermetatarsal space. The interdigital nerve was then resected, and the lengths of the cut nerves were compared based on the retractor employed.

Results: The mean length of proximal resection in the second intermetatarsal space was 2.42 cm when using the laminar spreader and 1.93 cm when using the Gelpi retractor (P = .252). In the third intermetatarsal space, the mean length of proximal resection was 2.14 cm when using the Laminar spreader and 1.48 cm when using the Gelpi retractor (P = .166).

Conclusion: This study demonstrates how far proximal the interdigital nerve is resected during a dorsal approach to Morton's neuroma and shows no statistically significant difference between the Laminar spreader and the Gelpi retractor. Level V: Cadaver study.
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http://dx.doi.org/10.1177/1938640018790013DOI Listing
June 2019

Ibrutinib Therapy and Skin and Soft Tissue Infection.

Open Forum Infect Dis 2018 Jul 18;5(7):ofy168. Epub 2018 Jul 18.

Infectious Diseases Section, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio.

Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase approved for the treatment of B-cell malignancies. There is growing concern about the risk of opportunistic infections following ibrutinib therapy. Herein, we describe the first case of skin and soft tissue infection in a patient receiving ibrutinib and recount the challenges in treating this infection.
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http://dx.doi.org/10.1093/ofid/ofy168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065501PMC
July 2018

A Case of a Second Intermetatarsal Space Gouty Tophus with a Presentation Similar to a Morton's Neuroma.

Cureus 2018 May 14;10(5):e2620. Epub 2018 May 14.

Orthopaedic Surgery, University of Alabama at Birmingham, Birmingham, USA.

Non-infectious soft tissue lesions of the foot and ankle are relatively rare clinically. These include benign and malignant neoplasms, as well as non-neoplastic or pseudotumoral lesions such as ganglionic, synovial and epidermoid cysts, intermetatarsal and adventitious bursitis, inflammatory lesions like gouty tophi and rheumatoid nodules, Morton's neuroma, and granuloma annulare. A 48-year-old male with a history of medically treated tophaceous gout presented with left foot neuropathic pain and paresthesia, in the setting of a well-circumscribed soft tissue lesion of the second intermetatarsal space, suspected to be a Morton's neuroma. Magnetic resonance imaging (MRI) showed a 4.1 x 2.7 x 2.6 cm heterogeneous soft tissue mass containing multiple cystic areas. Excisional biopsy was performed and histologic examination revealed well-circumscribed nodules of amorphous material containing needle-shaped clefts, rimmed by histiocytes, and multinucleated giant cells consistent with a gouty tophus. This is the first case reported in the literature of an intermetatarsal gouty tophus causing neuropathic pain and paresthesia. While Morton's neuroma is the most common cause of this presentation, this case illustrates that other pseudotumoral lesions, such as a gouty tophus, may present similarly, and should be considered in the differential diagnosis. While most cases of tophaceous gout can be adequately treated with urate-lowering therapy, surgery may be indicated for tophi that do not resolve with medical treatment based upon symptom severity, compression of nearby structures, and functional impairment.
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http://dx.doi.org/10.7759/cureus.2620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044487PMC
May 2018

Linezolid pharmacokinetics in MDR-TB: a systematic review, meta-analysis and Monte Carlo simulation.

J Antimicrob Chemother 2018 07;73(7):1755-1762

Institute of Infection and Global Health, University of Liverpool, Liverpool, UK.

Objectives: The oxazolidinone linezolid is an effective component of drug-resistant TB treatment, but its use is limited by toxicity and the optimum dose is uncertain. Current strategies are not informed by clinical pharmacokinetic (PK)/pharmacodynamic (PD) data; we aimed to address this gap.

Methods: We defined linezolid PK/PD targets for efficacy (fAUC0-24:MIC >119 mg/L/h) and safety (fCmin <1.38 mg/L). We extracted individual-level linezolid PK data from existing studies on TB patients and performed meta-analysis, producing summary estimates of fAUC0-24 and fCmin for published doses. Combining these with a published MIC distribution, we performed Monte Carlo simulations of target attainment.

Results: The efficacy target was attained in all simulated individuals at 300 mg q12h and 600 mg q12h, but only 20.7% missed the safety target at 300 mg q12h versus 98.5% at 600 mg q12h. Although suggesting 300 mg q12h should be used preferentially, these data were reliant on a single centre. Efficacy and safety targets were missed by 41.0% and 24.2%, respectively, at 300 mg q24h and by 44.6% and 27.5%, respectively, at 600 mg q24h. However, the confounding effect of between-study heterogeneity on target attainment for q24h regimens was considerable.

Conclusions: Linezolid dosing at 300 mg q12h may retain the efficacy of the 600 mg q12h licensed dosing with improved safety. Data to evaluate commonly used 300 mg q24h and 600 mg q24h doses are limited. Comprehensive, prospectively obtained PK/PD data for linezolid doses in drug-resistant TB treatment are required.
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http://dx.doi.org/10.1093/jac/dky096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005026PMC
July 2018

Lineage-Determining Transcription Factor TCF-1 Initiates the Epigenetic Identity of T Cells.

Immunity 2018 02;48(2):243-257.e10

Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

T cell development is orchestrated by transcription factors that regulate the expression of genes initially buried within inaccessible chromatin, but the transcription factors that establish the regulatory landscape of the T cell lineage remain unknown. Profiling chromatin accessibility at eight stages of T cell development revealed the selective enrichment of TCF-1 at genomic regions that became accessible at the earliest stages of development. TCF-1 was further required for the accessibility of these regulatory elements and at the single-cell level, it dictated a coordinate opening of chromatin in T cells. TCF-1 expression in fibroblasts generated de novo chromatin accessibility even at chromatin regions with repressive marks, inducing the expression of T cell-restricted genes. These results indicate that a mechanism by which TCF-1 controls T cell fate is through its widespread ability to target silent chromatin and establish the epigenetic identity of T cells.
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http://dx.doi.org/10.1016/j.immuni.2018.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824646PMC
February 2018