The serine-rich repeat (SRR) glycoproteins are a family of adhesins found in many Gram-positive bacteria. Expression of the SRR adhesins has been linked to virulence for a variety of infections, including streptococcal endocarditis. The SRR preproteins undergo intracellular glycosylation, followed by export via the accessory Sec (aSec) system. This specialized transporter is comprised of SecA2, SecY2 and three to five accessory Sec proteins (Asps) that are required for export. Although the post-translational modification and transport of the SRR adhesins have been viewed as distinct processes, we found that Asp2 of Streptococcus gordonii also has an important role in modifying the SRR adhesin GspB. Biochemical analysis and mass spectrometry indicate that Asp2 is an acetyltransferase that modifies N-acetylglucosamine (GlcNAc) moieties on the SRR domains of GspB. Targeted mutations of the predicted Asp2 catalytic domain had no effect on transport, but abolished acetylation. Acetylated forms of GspB were only detected when the protein was exported via the aSec system, but not when transport was abolished by secA2 deletion. In addition, GspB variants rerouted to export via the canonical Sec pathway also lacked O-acetylation, demonstrating that this modification is specific to export via the aSec system. Streptococci expressing GspB lacking O-acetylated GlcNAc were significantly reduced in their ability bind to human platelets in vitro, an interaction that has been strongly linked to virulence in the setting of endocarditis. These results demonstrate that Asp2 is a bifunctional protein involved in both the post-translational modification and transport of SRR glycoproteins. In addition, these findings indicate that these processes are coordinated during the biogenesis of SRR glycoproteins, such that the adhesin is optimally modified for binding. This requirement for the coupling of modification and export may explain the co-evolution of the SRR glycoproteins with their specialized glycan modifying and export systems.

Failure of the right ventricle (RV) is a serious disease with a poor prognosis and limited treatment options. Signaling by α-adrenergic receptors (α-ARs), in particular the α-subtype, mediate cardioprotective effects in multiple heart failure models. Recent studies have shown that chronic treatment with the α-subtype agonist A61603 improves function and survival in a model of left ventricular failure. The goal of the present study was to determine if chronic A61603 treatment is beneficial in a RV failure model. We used tracheal instillation of the fibrogenic antibiotic bleomycin in mice to induce pulmonary fibrosis, pulmonary hypertension, and RV failure within 2 wk. Some mice were chronically treated with a low dose of A61603 (10 ng·kg·day). In the bleomycin model of RV failure, chronic A61603 treatment was associated with improved RV fractional shortening and greater in vitro force development by RV muscle preparations. Cell injury markers were reduced with A61603 treatment (serum cardiac troponin I, RV fibrosis, and expression of matrix metalloproteinase-2). RV oxidative stress was reduced (using the probes dihydroethidium and 4-hydroxynonenal). Consistent with lowered RV oxidative stress, A61603 was associated with an increased level of the cellular antioxidant superoxide dismutase 1 and a lower level of the prooxidant NAD(P)H oxidase isoform NOX4. In summary, in the bleomycin model of RV failure, chronic A61603 treatment reduced RV oxidative stress, RV myocyte necrosis, and RV fibrosis and increased both RV function and in vitro force development. These findings suggest that in the context of pulmonary fibrosis, the α-subtype is a potential therapeutic target to treat the failing RV. Right ventricular (RV) failure is a serious disease with a poor prognosis and no effective treatments. In the mouse bleomycin model of RV failure, we tested the efficacy of a treatment using the α-adrenergic receptor subtype agonist A61603. Chronic A61603 treatment improved RV contraction and reduced multiple indexes of RV injury, suggesting that the α-subtype is a therapeutic target to treat RV failure.

BACKGROUND

Management of patients with chronic conditions relies on accurate measurement. It is unknown how transition to the ICD-10 coding system affected reporting of chronic condition rates over time. We measured chronic condition rates 2 years before and 1 year after the transition to ICD-10 to examine changes in prevalence rates and potential measurement issues in the Veterans Affairs (VA) health care system.

METHODS

We developed definitions for 34 chronic conditions using ICD-9 and ICD-10 codes and compared the prevalence rates of these conditions from FY2014 to 2016 in a 20% random sample (1.0 million) of all VA patients. In each year we estimated the total number of patients diagnosed with the conditions. We regressed each condition on an indicator of ICD-10 (versus ICD-9) measurement to obtain the odds ratio associated with ICD-10.

RESULTS

Condition prevalence estimates were similar for most conditions before and after ICD-10 transition. We found significant changes in a few exceptions. Alzheimer's disease and spinal cord injury had more than twice the odds of being measured with ICD-10 compared to ICD-9. HIV/AIDS had one-third the odds, and arthritis had half the odds of being measured with ICD-10. Alcohol dependence and tobacco/nicotine dependence had half the odds of being measured in ICD-10.

CONCLUSION

Many chronic condition rates were consistent from FY14-16, and there did not appear to be widespread undercoding of conditions after ICD-10 transition. It is unknown whether increased sensitivity or undercoding led to decreases in mental health conditions.

Importance

High-risk medical devices often undergo modifications, which are approved by the US Food and Drug Administration (FDA) through various kinds of premarket approval (PMA) supplements. There have been multiple high-profile recalls of devices approved as PMA supplements.

Objective

To characterize the quality of the clinical studies and data (strength of evidence) used to support FDA approval of panel-track supplements (a type of PMA supplement pathway that is used for significant changes in a device or indication for use and always requires clinical data).

Design and Setting

Descriptive study of clinical studies supporting panel-track supplements approved by the FDA between April 19, 2006, and October 9, 2015.

Exposure

Panel-track supplement approval.

Main Outcomes and Measures

Methodological quality of studies including randomization, blinding, type of controls, clinical vs surrogate primary end points, use of post hoc analyses, and reporting of age and sex.

Results

Eighty-three clinical studies supported the approval of 78 panel-track supplements, with 71 panel-track supplements (91%) supported by a single study. Of the 83 studies, 37 (45%) were randomized clinical trials and 25 (30%) were blinded. The median number of patients per study was 185 (interquartile range, 75-305), and the median follow-up duration was 180 days (interquartile range, 84-270 days). There were a total of 150 primary end points (mean [SD], 1.8 [1.2] per study), and 57 primary end points (38%) were compared with controls. Of primary end points with controls, 6 (11%) were retrospective controls and 51 (89%) were active controls. One hundred twenty-one primary end points (81%) were surrogate end points. Thirty-three studies (40%) did not report age and 25 (30%) did not report sex for all enrolled patients. The FDA required postapproval studies for 29 of 78 (37%) panel-track supplements.

Conclusions and Relevance

Among clinical studies used to support FDA approval of high-risk medical device modifications, fewer than half were randomized, blinded, or controlled, and most primary outcomes were based on surrogate end points. These findings suggest that the quality of studies and data evaluated to support approval by the FDA of modifications of high-risk devices should be improved.

BACKGROUND

A low proportion of CD28CD8 T cells that express CD57 is associated with increased mortality in HIV infection. The effect of increasing body mass index (BMI) changes in the proportion of CD57CD28CD8 T cells among HIV-infected individuals on antiretroviral therapy is unknown.

SETTING

In a US cohort of HIV-infected women, we evaluated associations of BMI and waist circumference with 3 distinct CD8 T cell phenotypes: % CD28CD57CD8 T cells, % CD57 of CD28CD8 T cells, and % CD28 of all CD8 T cells.

METHODS

Multivariable linear regression analysis was used to estimate beta coefficients for each of 3 T-cell phenotypes. Covariates included HIV parameters (current and nadir CD4, current viral load), demographics (age, race, income, and study site), and lifestyle (tobacco and alcohol use) factors.

RESULTS

Of 225 participants, the median age was 46 years and 50% were obese (BMI >30 m/kg). Greater BMI and waist circumference were both associated with higher % CD28CD57CD8 T cells and % CD57 of all CD28CD8 T cells in multivariable analysis, including adjustment for HIV viral load (all P < 0.05). The association between greater BMI and the overall proportion of CD28 CD8 cells in fully adjusted models (0.078, 95% confidence interval: -0.053 to 0.209) was not significant.

CONCLUSIONS

In this analysis, greater BMI and waist circumference are associated with greater expression of CD57 on CD28CD8 T cells and a greater proportion of CD57CD28 CD8 T cells. These findings may indicate that increasing BMI is immunologically protective in HIV-infected women. Future research is needed to understand the prognostic importance of these associations on clinical outcomes.