Reduced synthesis of phospho-polysaccharide in Lactococcus as a strategy to evade phage infection.

Lactococcus spp. are applied routinely in dairy fermentations and their consistent growth and associated acidification activity is critical to ensure the quality and safety of fermented dairy foods. Bacteriophages pose a significant threat to such fermentations and thus it is imperative to study how these bacteria may evade their viral predators in the relevant confined settings. Many lactococcal phages are known to specifically recognise and bind to cell wall polysaccharides (CWPSs) and particularly the phospho-polysaccharide (PSP) side chain component that is exposed on the host cell surface. In the present study, we generated derivatives of a lactococcal strain with reduced phage sensitivity to establish the mode of phage evasion. The resulting mutants were characterized using a combination of comparative genome analysis, microbiological and chemical analyses. Using these approaches, it was established that the phage-resistant derivatives incorporated mutations in genes within the cluster associated with CWPS biosynthesis resulting in growth and morphological defects that could revert when the selective pressure of phages was removed. Furthermore, the cell wall extracts of selected mutants revealed that the phage-resistant strains produced intact PSP but in significantly reduced amounts. The reduced availability of the PSP and the ability of lactococcal strains to revert rapidly to wild type growth and activity in the absence of phage pressure provides Lactococcus with the means to survive and evade phage attack.

Calcimimetic Use in Dialysis-Dependent Medicare Fee-for-Service Beneficiaries and Implications for Bundled Payment.

Background: Patients who are dialysis dependent and have secondary hyperparathyroidism (SHPT) may require calcimimetics to reduce parathyroid hormone levels to treatment goals. Medicare currently uses the Transitional Drug Add-on Payment Adjustment (TDAPA) designation under the ESKD Prospective Payment System ("bundled payment") to pay for calcimimetics (the first products eligible for the adjustment); this payment designation for calcimimetics is expected to conclude after 2020. This study explores variability in calcimimetic use across key patient characteristics and its potential effect on policy options for incorporating calcimimetics permanently into the bundle. Methods: This descriptive analysis used the 100% sample of Medicare FFS Part B (outpatient) 2018 claims to describe national-, regional-, and patient-level variation (including race, dual eligibility, and dialysis vintage) in calcimimetic use among beneficiaries who are dialysis dependent. Results: A total of 373,874 beneficiaries were analyzed, 28% had ≥90 days of calcimimetic use during 2018. At the national level, the proportion of patients on dialysis using calcimimetics was roughly 80% higher in Black versus non-Black patients on dialysis, 30% higher in patients on dialysis who were dual eligible versus non-dual eligible, and three times higher in patients with a dialysis vintage ≥3 years versus <3 years (all results unadjusted). Calcimimetic use was similar across census regions, however, substantial variation in calcimimetic use was observed at the facility level. Medicare spending for calcimimetic therapies as a proportion of total Medicare dialysis spending was >10% in approximately 20% of dialysis facilities. Conclusions: Although less than a third of beneficiaries use calcimimetics, certain patient-level characteristics are associated with higher rates of maintenance calcimimetic use. Due to the financial pressure many dialysis facilities face, how calcimimetics are incorporated into the bundle may have a direct effect on facility reimbursement for, and patient access to, therapy. Careful consideration will be required to ensure patients who are vulnerable and require treatment for SHPT do not face barriers to appropriate care.