Orthopedic Implant-Associated and Central Venous Catheter-Associated Infections Caused by Microbacterium spp. in the Veterans Affairs Healthcare System from 2000 to 2020.

Background: A 72-year-old male developed a late-onset infection of an internal fixation device caused by Microbacterium oxydans. Although often considered contaminants, bacteria from the genus Microbacterium may also be pathogens. We also summarize cases from the Veteran Health Administration (VHA) from which Microbacterium isolates were recovered and review the relevant literature. Patients and Methods: Using the national VHA database, we identified patients with cultures that grew Microbacterium spp. We also review published clinical reports describing Microbacterium spp. as a cause of infections. Results: Between January 2000 and September 2020, 18 cases had Microbacterium spp. Of those, Microbacterium isolates were regarded as pathogens for seven cases; all involved prosthetic material that was consequently removed. Two patients had internal fixation devices whereas the remaining five were patients with a central venous catheter. Conclusions: For patients with prosthetic material, recovery of Microbacterium spp. from device-related clinical cultures should prompt consideration of device removal when possible.

Adding a Physical Therapist to the Health Care Team in an HIV Clinic Increases Physical Therapy Referrals and Reduces Opioid Prescriptions Provided for Chronic Musculoskeletal Pain in Patients Living With HIV.

BACKGROUND: Musculoskeletal (MSK) pain is common in people living with HIV (PLWH). Health care providers sometimes prescribe opioids to control pain, which may lead to opioid misuse. An interdisciplinary approach that includes physical therapy has been successful in managing MSK pain in various health care settings. Therefore, we sought to find the impact of recruiting a physical therapist (PT) on the number of opioid prescriptions and physical therapy referrals made by physicians in training to manage MSK pain in PLWH. METHODS: We performed a retrospective chart review of patients seen by Internal Medicine physicians in training in an HIV clinic in Detroit before (2017) and after (2018) recruiting a PT to the health care team and collected demographic and clinical data. We also surveyed the trainees to assess how the PT addition influenced their learning. Institutional review board waiver was obtained. RESULTS: Results showed that of all PLWH seen at the clinic, 28/249 (11%) and 37/178 (21%) had chronic MSK pain in the 2017 and 2018 data sets, respectively. In 2017, all 28 patients with MSK pain were prescribed opioids. This decreased in 2018 after the PT addition (10/37 patients; P < .0001). The number of physical therapy referrals significantly increased after the PT addition (2017: 5/28 patients; 2018: 17/37 patients; P = .03). Trainees felt that the PT helped improve their examination skills and develop a treatment plan for patients. CONCLUSIONS: The addition of a PT encouraged physicians in training to utilize nonopioid management of MSK pain in PLWH and enhanced their learning experience, as perceived by the trainees.

Concurrent chemoradiotherapy with weekly versus triweekly cisplatin in locally advanced squamous cell carcinoma of the head and neck: Comparative analysis.

BACKGROUND: Cisplatin-based chemoradiotherapy is standard of care for locally advanced squamous cell carcinoma of the head and neck. This systemic review compared efficacy and safety of weekly vs triweekly cisplatin in locally advanced squamous cell carcinoma of the head and neck. METHODS: Among 1500 prospective studies published from 1970 to 2015, 39 (18 weekly, 21 triweekly) including 3668 patients qualified for inclusion. Clinical outcomes were analyzed using weighted estimates and 2-tailed t test for comparisons; significance level was 0.05. RESULTS: Locoregional control was 58% (CI 53%-63%) vs 61% (CI 56%-65%; P = .7). The 2-year overall survival (OS) was 74% (CI 66%-80%) for weekly vs 67% (64%-69%) triweekly groups (P = .67). The 2-year progression-free survival (PFS) was 69% (CI 59%-77%) for weekly vs 62% (CI 58%-65%) triweekly groups (P = .9). Grade 3 to 5 toxicities were 36% vs 40% (P = .37) in weekly vs triweekly groups. CONCLUSIONS: Weekly cisplatin was comparable in efficacy and safety to the triweekly regimen. Our analysis supports the use of weekly or triweekly cisplatin in locally advanced squamous cell carcinoma of the head and neck, with tolerability being a key factor in selection.

Clinical Impact of PI3K/BRAF Mutations in RAS Wild Metastatic Colorectal Cancer: Meta-analysis Results.

BACKGROUND: Understanding the molecular mechanisms of colorectal cancer has evolved during the last decade ushering the era of personalized medicine. Alteration of BRAF and PI3K is common in colorectal cancer, and can affect several signaling pathways including EGFR (epidermal growth factor receptor). The aim of this meta-analysis is to evaluate the clinical role of PI3K and BRAF mutations in patients with KRAS wild-type metastatic colorectal cancer (MCRC) receiving an EGFR monoclonal antibody (anti-EGFR) inhibitor as first-line therapy. METHODS: A literature search was performed to identify studies exploring the association between PI3K/BRAF mutations and clinical outcomes of KRAS wild-type mCRC patients treated with anti-EGFR as a first-line therapy. The primary clinical outcome was overall response rate (ORR). The secondary outcomes included progression-free survival (PFS) and overall survival (OS). The pooled relative risk (RR) or hazard ratio (HR) was estimated by using fixed-effect model or random effect model according to heterogeneity between studies. RESULTS: Ten studies with 1470 mCRC patients (357 for PI3K studies and 1113 from BRAF studies) met selection criteria. We observed a trend towards lower ORR in patients with PI3K mutations (3 studies, 357 patients; ORR = 14.3% in mutant-type PI3K vs. 52.4% in wild-type PIK3CA [95% CI - 0.12-0.02]; P = 0.13). Patients with mutant-type PI3K have significant shorter PFS (3 studies, 357 patients, 3.8 vs. 4.15 months, HR = 1.36; [95% CI 1.04-1.77]; P = 0.02]), and OS (3 studies, 357 patients, 14.17 vs. 16.3 months, HR = 1.50; [95% CI 1.14-1.97]; P = 0.004) compared to those with wild PI3K. For BRAF, patients with mutant type have significantly lower ORR (7 studies, 1113 patients; ORR = 33% vs. 39%; [95% CI - 0.16-0.01]; P = 0.03), shorter PFS (5 studies, 814 patients, 3.9 vs. 5.7 months, HR = 1.72; [95% CI 1.47-2.01]; P = 0.00001), and shorter OS (4 studies, 766 pts., 9.1 vs. 18.9 months, HR = 1.22; [95% CI 1.04-1.44]; P = 0.01) compared to those with wild-type. CONCLUSION: This analysis suggests that patients with mCRC and either PI3K or BRAF mutation may have a lower response and worse outcome when treated with anti-EGFR in the first line. Given their worse outcome, routine testing for BRAF and PI3K mutational status should be considered. Novel therapeutic approaches are needed for patients with mutations in BRAF or PI3K.

Blocking of PDL-1 interaction enhances primary and secondary CD8 T cell response to herpes simplex virus-1 infection.

The blocking of programmed death ligand-1 (PDL-1) has been shown to enhance virus-specific CD8 T cell function during chronic viral infections. Though, how PDL-1 blocking at the time of priming affects the quality of CD8 T cell response to acute infections is not well understood and remains controversial. This report demonstrates that the magnitude of the primary and secondary CD8 T cell responses to herpes simplex virus-1 (HSV-1) infection is subject to control by PDL-1. Our results showed that after footpad HSV-1 infection, PD-1 expression increases on immunodominant SSIEFARL peptide specific CD8 T cells. Additionally, post-infection, the level of PDL-1 expression also increases on CD11c+ dendritic cells. Intraperitoneal administration of anti-PDL-1 monoclonal antibody given one day prior to and three days after cutaneous HSV-1 infection, resulted in a marked increase in effector and memory CD8 T cell response to SSIEFARL peptide. This was shown by measuring the quantity and quality of SSIEFARL-specific CD8 T cells by making use of ex-vivo assays that determine antigen specific CD8 T cell function, such as intracellular cytokine assay, degranulation assay to measure cytotoxicity and viral clearance. Our results are discussed in terms of the beneficial effects of blocking PDL-1 interactions, while giving prophylactic vaccines, to generate a more effective CD8 T cell response to viral infection.

Substance P in the corneal stroma regulates the severity of herpetic stromal keratitis lesions.

PURPOSE: To determine whether substance P (SP) in herpes simplex virus-1 (HSV-1) infected cornea regulates the severity of herpetic stromal keratitis (HSK) lesions in a mouse model. METHODS: C57BL/6 mice were infected ocularly with HSV-1 (RE). The corneas with HSK lesions, on Day 15 postinfection, were grouped on the basis of the corneal opacity as mild (≤2) or severe (>2). The amount of SP was determined in the corneas with mild or severe HSK lesions by enzyme immunosorbent assay (EIA) and confocal microscopy. Subconjunctival inoculation of spantide I, SP receptor antagonist, was carried out during the clinical phase of HSK. ELISA and flow cytometry were used to determine the level of cytokines, chemokines, and influx of immune cell types in the corneal lesions. RESULTS: The authors determined a significantly higher level of SP in the corneas with severe HSK lesions in comparison with mild lesions. The corneas with a higher level of SP also exhibited higher amounts of proinflammatory cytokines (IL-6, IFN-γ) and chemokines (CCL3, CXCL2) when compared with the corneas with a lower level of SP. SP receptor NK1R expression was determined in CD45- and CD45+ cells in infected cornea. SP present in the corneal stroma of the eyes with severe HSK lesions colocalized with ß-III tubulin(+) and IA(b+) cell types. Subconjunctival inoculation of spantide I during the clinical phase of HSK resulted in significant reduction in the corneal opacity and angiogenesis. CONCLUSIONS: Collectively, these results demonstrate the relative contribution of substance P in regulating the clinical severity of HSK lesions in a mouse model.

Advancing age leads to predominance of inhibitory receptor expressing CD4 T cells.

Decline in CD4 T cell function is the hallmark of aging. In this study, we compared the proportion and absolute number of inhibitory receptor expressing splenic CD4 T cells in unprimed young (2 months) and aged (20 months) C57BL/6 mice. Our results showed a predominance of PD-1, ICOS and CTLA-4 expressing conventional and regulatory CD4 T cells in aged mice. Furthermore, the expression of these molecules was localized to memory but not naïve CD4 T cell subset. Since aging is associated with decline in naïve but accumulation of hyporesponsive memory phenotype (MP) CD4 T cell, we hypothesize that inhibitory receptors can account for the senescence noted in MP subset of CD4 T cell.

Nuclear magnetic resonance and biochemical measurements of glucose utilization in the cone-dominant ground squirrel retina.

PURPOSE: To provide quantitative information on glucose utilization in cone-dominant ground squirrel retinas. METHODS: Ground squirrel eyecups were incubated in medium containing (14)C-glucose, and the production of (14)CO(2) was measured. Measurements were also made of lactic acid production (glycolysis). Nuclear magnetic resonance (NMR) was used to track metabolites generated from (13)C-1 glucose. RESULTS: Ground squirrel eyecups produced lactate at a high rate and exhibited normal histology. Light-adaptation reduced glycolysis by 20%. Ouabain decreased glycolysis by 25% and decreased (14)CO(2) production by 60%. Blockade of glutamate receptors had little effect on the glycolysis and (14)CO(2) produced. When metabolic responses were restricted to photoreceptors, light caused a 33% decrease in (14)CO(2) production. The rate of (14)CO(2) production was less than 10% of lactate production. Lactate was the major product formed from (13)C-glucose. Other (13)C-labeled compounds included glutamate, aspartate, glutamine, alanine, taurine, and GABA. Lactate was the only product detected in the medium bathing the ground squirrel retinas. The rod-dominant rat retina exhibited a similar pattern of metabolites formed from glucose. CONCLUSIONS: Lactate, not CO(2), is the major product of glucose metabolism in both ground squirrel and rat retinas. Active Na(+) transport, however, depends more on ATP produced by mitochondria than by glycolysis. A relatively high fraction of ATP production from glycolysis and glucose oxidation continues in the absence of active Na(+) pumping and glutamatergic transmission. Major neurotransmitters are synthesized from the aerobic metabolism of glucose; anoxia-induced impairment in retinal synaptic transmission may be due to depletion of neurotransmitters.