Sepsis Among Medicare Beneficiaries: 4. Precoronavirus Disease 2019 Update January 2012-February 2020.

OBJECTIVES: To provide updated information on the burdens of sepsis during acute inpatient admissions for Medicare beneficiaries. DESIGN: Analysis of paid Medicare claims via the Centers for Medicare and Medicaid Services DataLink Project. SETTING: All U.S. acute-care hospitals, excluding federally operated hospitals (Veterans Administration and Defense Health Agency). PATIENTS: All Medicare beneficiaries, January 2012-February 2020, with an explicit sepsis diagnostic code assigned during an inpatient admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The count of Medicare Part A/B (fee-for-service) plus Medicare Advantage inpatient sepsis admissions rose from 981,027 (CY2012) to 1,700,433 (CY 2019). The proportion of total admissions with sepsis in the Medicare Advantage population rose from 21.43% to 35.39%, reflecting the increasing beneficiary proportion enrolled in Medicare Advantage. In CY2019, 6-month mortality rates in Medicare fee-for-service beneficiaries for sepsis continued to decline, but remained high: 59.9% for septic shock, 35.5% for severe sepsis, 30.8% for sepsis attributed to a specific organism, and 26.5% for unspecified sepsis. Total fee-for-service-only inpatient hospital costs rose from $17.79B (CY2012) to $22.98B (CY2019). We estimated that the aggregate cost of sepsis hospital care for the entire U.S. population was at least $57.47B in 2019. Inclusion of 14 months' (January 2019-February 2020) newer data exposed new trends: the cost per patient, number of admissions, and fraction of patients with sepsis labeled as present on admission inflected around November 2015, coincident with the change to International Classification of Diseases, 10th Edition, and introduction of the Severe Sepsis and Septic Shock Management Bundle (SEP-1) metric. CONCLUSIONS: Sepsis among Medicare beneficiaries precoronavirus disease 2019 imposed immense burdens upon patients, their families, and the taxpayers.

Sepsis Among Medicare Beneficiaries: 1. The Burdens of Sepsis, 2012-2018.

OBJECTIVES: To provide contemporary estimates of the burdens (costs and mortality) associated with acute inpatient Medicare beneficiary admissions for sepsis. DESIGN: Analysis of paid Medicare claims via the Centers for Medicare & Medicaid Services DataLink Project. SETTING: All U.S. acute care hospitals, excluding federally operated hospitals (Veterans Administration and Defense Health Agency). PATIENTS: All Medicare beneficiaries, 2012-2018, with an inpatient admission including one or more explicit sepsis codes. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Total inpatient hospital and skilled nursing facility admission counts, costs, and mortality over time. From calendar year (CY)2012-CY2018, the total number of Medicare Part A/B (fee-for-service) beneficiaries with an inpatient hospital admission associated with an explicit sepsis code rose from 811,644 to 1,136,889. The total cost of inpatient hospital admission including an explicit sepsis code for those beneficiaries in those calendar years rose from $17,792,657,303 to $22,439,794,212. The total cost of skilled nursing facility care in the 90 days subsequent to an inpatient hospital discharge that included an explicit sepsis code for Medicare Part A/B rose from $3,931,616,160 to $5,623,862,486 over that same interval. Precise costs are not available for Medicare Part C (Medicare Advantage) patients. Using available federal data sources, we estimated the aggregate cost of inpatient admissions and skilled nursing facility admissions for Medicare Advantage patients to have risen from $6.0 to $13.4 billion over the CY2012-CY2018 interval. Combining data for fee-for-service beneficiaries and estimates for Medicare Advantage beneficiaries, we estimate the total inpatient admission sepsis cost and any subsequent skilled nursing facility admission for all (fee-for-service and Medicare Advantage) Medicare patients to have risen from $27.7 to $41.5 billion. Contemporary 6-month mortality rates for Medicare fee-for-service beneficiaries with a sepsis inpatient admission remain high: for septic shock, approximately 60%; for severe sepsis, approximately 36%; for sepsis attributed to a specific organism, approximately 31%; and for unspecified sepsis, approximately 27%. CONCLUSION: Sepsis remains common, costly to treat, and presages significant mortality for Medicare beneficiaries.

Sepsis Among Medicare Beneficiaries: 2. The Trajectories of Sepsis, 2012-2018.

OBJECTIVES: To distinguish characteristics of Medicare beneficiaries who will have an acute inpatient admission for sepsis from those who have an inpatient admission without sepsis, and to describe their further trajectories during and subsequent to those inpatient admissions. DESIGN: Analysis of paid Medicare claims via the Centers for Medicare and Medicaid Services DataLink Project. SETTING: All U.S. acute care hospitals, excepting federal hospitals (Veterans Administration and Defense Health Agency). PATIENTS: Medicare beneficiaries, 2012-2018, with an inpatient hospital admission including one or more explicit sepsis codes. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Prevalent diagnoses in the year prior to the inpatient admission; healthcare contacts in the week prior to the inpatient admission; discharges, transfers, readmissions, and deaths (trajectories) for 6 months following discharge from the inpatient admission. Beneficiaries with no sepsis inpatient hospital admission for a year prior to an index hospital admission for sepsis were nearly indistinguishable by accumulated diagnostic codes from beneficiaries who had an index hospital admission without sepsis. Although the timing of healthcare services in the week prior to inpatient hospital admission was similar among beneficiaries who would be admitted for sepsis versus those whose inpatient admission did not include a sepsis code, the setting differed: beneficiaries destined for a sepsis admission were more likely to have received skilled nursing or unskilled nursing (e.g., nursing aide for activities of daily living) care. In contrast, comparing beneficiaries who had been free of any inpatient admission for an entire year and then required an inpatient admission, acute inpatient stays that included a sepsis code led to more than three times as many deaths within 1 week of discharge, with more admissions to skilled nursing facilities and fewer discharges to home. Comparing all beneficiaries who were admitted to a skilled nursing facility after an inpatient hospital admission, those who had sepsis coded during the index admission were more likely to die in the skilled nursing facility; more likely to be readmitted to an acute inpatient hospital and subsequently die in that setting; or if they survive to discharge from the skilled nursing facility, they are more likely to go next to a custodial nursing home. CONCLUSIONS: Although Medicare beneficiaries destined for an inpatient hospital admission with a sepsis code are nearly indistinguishable by other diagnostic codes from those whose admissions will not have a sepsis code, their healthcare trajectories following the admission are worse. This suggests that an inpatient stay that included a sepsis code not only identifies beneficiaries who were less resilient to infection but also signals increased risk for worsening health, for mortality, and for increased use of advanced healthcare services during and postdischarge along with an increased likelihood of an inpatient hospital readmission.

Sepsis Among Medicare Beneficiaries: 3. The Methods, Models, and Forecasts of Sepsis, 2012-2018.

OBJECTIVE: To evaluate the impact of sepsis, age, and comorbidities on death following an acute inpatient admission and to model and forecast inpatient and skilled nursing facility costs for Medicare beneficiaries during and subsequent to an acute inpatient sepsis admission. DESIGN: Analysis of paid Medicare claims via the Centers for Medicare & Medicaid Services DataLink Project (CMS) and leveraging the CMS-Hierarchical Condition Category risk adjustment model. SETTING: All U.S. acute care hospitals, excepting federal hospitals (Veterans Administration and Defense Health Agency). PATIENTS: All Part A/B (fee-for-service) Medicare beneficiaries with an acute inpatient admission in 2017 and who had no inpatient sepsis admission in the prior year. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Logistic regression models to determine covariate risk contribution to death following an acute inpatient admission; conventional regression to predict Medicare beneficiary sepsis costs. Using the Hierarchical Condition Category risk adjustment model to illuminate influence of illness on outcome of inpatient admissions, representative odds ratios (with 95% CIs) for death within 6 months of an admission (referenced to beneficiaries admitted but without the characteristic) are as follows: septic shock, 7.27 (7.19-7.35); metastatic cancer and acute leukemia (Hierarchical Condition Category 8), 6.76 (6.71-6.82); all sepsis, 2.63 (2.62-2.65); respiratory arrest (Hierarchical Condition Category 83), 2.55 (2.35-2.77); end-stage liver disease (Hierarchical Condition Category 27), 2.53 (2.49-2.56); and severe sepsis without shock, 2.48 (2.45-2.51). Models of the cost of sepsis care for Medicare beneficiaries forecast arise approximately 13% over 2 years owing the rising enrollments in Medicare offset by the cost of care per admission. CONCLUSIONS: A sepsis inpatient admission is associated with marked increase in risk of death that is comparable to the risks associated with inpatient admissions for other common and serious chronic illnesses. The aggregate costs of sepsis care for Medicare beneficiaries will continue to increase.

Economic Incentives for Antibacterial Drug Development: Literature Review and Considerations From the Transatlantic Task Force on Antimicrobial Resistance.

The Trans-Atlantic Task Force on Antimicrobial Resistance (TATFAR) in 2015 was tasked with exploring economic incentives for antibacterial drug development and providing recommendations for potential global implementation. Due to the continual decline of pharmaceutical companies investing in new antibiotic development and the rise in antimicrobial resistance, there is an urgent need to examine market mechanisms that are appropriate to encourage small, medium, and large companies to reinvest in this space. This review provides a summary of the various models that have been proposed and highlights positions posed by several policy documents, peer-reviewed publications, organization proposals, and government-sponsored reviews. The findings support a form of a de-linkage model and a combination of push and pull incentive mechanisms. This level of consensus could culminate in global coordination of incentives that strike a balance of rewarding innovation and ensuring appropriate antibiotic use.

A framework for future national pediatric pandemic respiratory disease severity triage: The HHS pediatric COVID-19 data challenge.

Introduction: With persistent incidence, incomplete vaccination rates, confounding respiratory illnesses, and few therapeutic interventions available, COVID-19 continues to be a burden on the pediatric population. During a surge, it is difficult for hospitals to direct limited healthcare resources effectively. While the overwhelming majority of pediatric infections are mild, there have been life-threatening exceptions that illuminated the need to proactively identify pediatric patients at risk of severe COVID-19 and other respiratory infectious diseases. However, a nationwide capability for developing validated computational tools to identify pediatric patients at risk using real-world data does not exist. Methods: HHS ASPR BARDA sought, through the power of competition in a challenge, to create computational models to address two clinically important questions using the National COVID Cohort Collaborative: (1) Of pediatric patients who test positive for COVID-19 in an outpatient setting, who are at risk for hospitalization? (2) Of pediatric patients who test positive for COVID-19 and are hospitalized, who are at risk for needing mechanical ventilation or cardiovascular interventions? Results: This challenge was the first, multi-agency, coordinated computational challenge carried out by the federal government as a response to a public health emergency. Fifty-five computational models were evaluated across both tasks and two winners and three honorable mentions were selected. Conclusion: This challenge serves as a framework for how the government, research communities, and large data repositories can be brought together to source solutions when resources are strapped during a pandemic.

Applying Lessons Learned From COVID-19 Therapeutic Trials to Improve Future ALI/ARDS Trials.

Host-directed therapeutics targeting immune dysregulation are considered the most promising approach to address the unmet clinical need for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) related to coronavirus disease 2019 (COVID-19). To better understand the current clinical study landscape and gaps in treating hospitalized patients with severe or critical COVID-19, we identified COVID-19 trials developing host-directed therapies registered at ClinicalTrials.gov and discussed the factors contributing to the success vs failure of these studies. We have learned, instead of the one-size-fits-all approach, future clinical trials evaluating a targeted immunomodulatory agent in heterogeneous patients with ALI/ARDS due to COVID-19 or other infectious diseases can use immune-based biomarkers in addition to clinical and demographic characteristics to improve patient stratification and inform clinical decision-making. Identifying distinct patient subgroups based on immune profiles across the disease trajectory, regardless of the causative pathogen, may accelerate evaluating host-directed therapeutics in trials of ALI/ARDS and related conditions (eg, sepsis).

Seasonal influenza vaccination is associated with reduced risk of death among Medicare beneficiaries☆.

BACKGROUND: Influenza causes substantial mortality, especially among older persons. Influenza vaccines are rarely more than 50% effective and rarely reach more than half of the US Medicare population, which is primarily an aged population. We wished to estimate the association between vaccination and mortality reduction. METHOD: We used the US Center for Medicare and Medicaid Services (CMS) DataLink Project to determine vaccination status and timing during the 2017-2018 influenza season for more than 26 million Medicare enrollees. Patient-level demographic, health, co-morbidity, hospitalization, vaccination, and healthcare utilization claims data were supplied as covariates to general linear models in order to isolate and estimate the association between participation in the vaccination program and relative risk of death. FINDINGS: The 2017-2018 seasonal influenza vaccine reduced (Relative Risk Ratio [RRR] 0.936 [95% CI = 0.918-0.954]) the risk of all-cause death among beneficiaries following a hospitalization for sepsis and moreover the risk of death without a prior hospitalization during the 2.5-month outcome window (RRR 0.870 [95% CI = 0.853-0.887]). We estimate the number needed to vaccinate (NNV) to prevent a death in the ten-week outcome window is between 1,515 beneficiaries (95% CI = 1,351-1,754; derived from the average treatment effect of augmented inverse probability weighting) and 1,960 beneficiaries (95% CI = 1,695-2,381; derived from the average marginal effect of logistic regression). Among beneficiaries requiring hospitalization, the greatest death risk reduction accrued to those 85 + years of age who were hospitalized with sepsis, RRR 0.92 [95% CI = 0.89-0.95]. No apparent benefit was realized by beneficiaries who required custodial (nursing home) care. INTERPRETATION: Seasonal influenza immunization is associated with relative reduction of death risk among non-institutionalized Medicare beneficiaries. FUNDING: All authors are full-time or contractual employees of the United States Federal Government, Department of Health and Human Services, the funding agency.

Evidence for novel beta-sheet structures in Iowa mutant beta-amyloid fibrils.

Asp23-to-Asn mutation within the coding sequence of beta-amyloid, called the Iowa mutation, is associated with early onset, familial Alzheimer's disease and cerebral amyloid angiopathy, in which patients develop neuritic plaques and massive vascular deposition predominantly of the mutant peptide. We examined the mutant peptide, D23N-Abeta40, by electron microscopy, X-ray diffraction, and solid-state NMR spectroscopy. D23N-Abeta40 forms fibrils considerably faster than the wild-type peptide (k = 3.77 x 10(-3) min(-1) and 1.07 x 10(-4) min(-1) for D23N-Abeta40 and the wild-type peptide WT-Abeta40, respectively) and without a lag phase. Electron microscopy shows that D23N-Abeta40 forms fibrils with multiple morphologies. X-ray fiber diffraction shows a cross-beta pattern, with a sharp reflection at 4.7 A and a broad reflection at 9.4 A, which is notably smaller than the value for WT-Abeta40 fibrils (10.4 A). Solid-state NMR measurements indicate molecular level polymorphism of the fibrils, with only a minority of D23N-Abeta40 fibrils containing the in-register, parallel beta-sheet structure commonly found in WT-Abeta40 fibrils and most other amyloid fibrils. Antiparallel beta-sheet structures in the majority of fibrils are indicated by measurements of intermolecular distances through (13)C-(13)C and (15)N-(13)C dipole-dipole couplings. An intriguing possibility exists that there is a relationship between the aberrant structure of D23N-Abeta40 fibrils and the unusual vasculotropic clinical picture in these patients.

Peptide-based inhibitors of amyloid assembly.

This review considers the design, synthesis, and mechanistic assessment of peptide-based fibrillogenesis inhibitors, mainly focusing on beta-amyloid, but generalizable to other aggregating proteins and peptides. In spite of revision of the "amyloid hypothesis," the investigation and development of fibrillogenesis inhibitors remain important scientific and therapeutic goals for at least three reasons. First, it is still premature to dismiss fibrils altogether as sources of cytotoxicity. Second, a "fibrillogenesis inhibitor" is typically identified experimentally as such, but these compounds may also bind to intermediates in the fibrillogenesis pathway and have hard-to-predict consequences, including improved clearance of more cytotoxic soluble oligomers. Third, inhibitors are valuable structural probes, as the entire field of enzymology attests. Screening procedures for selection of random inhibitory sequences are briefly considered, but the bulk of the review concentrates on rationally designed fibrillogenesis inhibitors. Among these are internal segments of fibril-forming peptides, amino acid substitutions and side chain modifications of fibrillogenic domains, insertion of prolines into or adjacent to fibrillogenic domains, modification of peptide termini, modification of peptide backbone atoms (including N-methylation), peptide cyclization, use of D-amino acids in fibrillogenic domains, and nonpeptidic beta-sheet mimics. Finally, we consider methods of assaying fibrillogenesis inhibitors, including pitfalls in these assays. We consider binding of inhibitor peptides to their targets, but because this is a specific application of the more general and much larger problem of assessing protein-protein interactions, this topic is covered only briefly. Finally, we consider potential applications of inhibitor peptides to therapeutic strategies.

Spatial separation of beta-sheet domains of beta-amyloid: disruption of each beta-sheet by N-methyl amino acids.

In a recent model of beta-amyloid (Abeta) fibrils, based mainly on solid-state NMR data, a molecular layer consists of two beta-sheets (residues 12-23 and 31-40 of Abeta1-40), folded onto one another by a connecting "bend" structure (residues 25-29) in the side-chain dimension. In this paper, we use two N-methyl amino acids to disrupt each of the two beta-sheets individually (2NMe(NTerm), residues 17 and 19; and 2NMe(CTerm), residues 37 and 39), or both of them at the same time (4NMe, with the above four N-methylated residues). Our data indicate that incorporation of two N-methyl amino acids into one beta-sheet is sufficient to disrupt that sheet while leaving the other, unmodified beta-sheet intact and able to form fibrils. We show, however, that disruption of each of the two beta-sheets has strikingly different effects on fibrillogenesis kinetics and fibril morphology. Both 2NMe(NTerm) and 2NMe(CTerm) form fibrils at similar rates, but more slowly than that of unmodified Abeta1-40. Electron microscopy shows that 2NMe(NTerm) forms straight fibrils with fuzzy amorphous material coating the edges, while 2NMe(CTerm) forms very regular, highly twisted fibrils-in both cases, distinct from the morphology of Abeta1-40 fibrils. Both 2NMe peptides show a "CMC" approximately four times greater than that of Abeta1-40. CD spectra of these peptides also evolve differently in time: whereas the CD spectra of 2NMe(NTerm) evolve little over 10 days, those of 2NMe(CTerm) show a transition to high beta-sheet content at about day 4-5. We also show that disruption of both beta-sheet domains, as in 4NMe, prevents fibril formation altogether, and renders Abeta1-40 highly water soluble and monomeric, and with solvent-exposed side chains. In summary, our data show (1) that the two beta-sheet domains fold in a semiautonomous manner, since disrupting each one still allows the other to fold; (2) that disruption of the N-terminal beta-sheet has a more profound effect on fibrillogenesis than disruption of the C-terminal beta-sheet, suggesting that the former is the more critical for the overall structure of the fibril; and (3) that disruption of both beta-sheet domains renders the peptide monomeric and unable to form fibrils.

Abeta40-Lactam(D23/K28) models a conformation highly favorable for nucleation of amyloid.

Recent solid-state NMR data (1) demonstrate that Abeta(1)(-)(40) adopts a conformation in amyloid fibrils with two in-register, parallel beta-sheets, connected by a bend structure encompassing residues D(23)VGSNKG(29), with a close contact between the side chains of Asp23 and Lys28. We hypothesized that forming this bend structure might be rate-limiting in fibril formation, as indicated by the lag period typically observed in the kinetics of Abeta(1)(-)(40) fibrillogenesis. We synthesized Abeta(1)(-)(40)-Lactam(D23/K28), a congener Abeta(1)(-)(40) peptide that contains a lactam bridge between the side chains of Asp23 and Lys28. Abeta(1)(-)(40)-Lactam(D23/K28) forms fibrils similar to those formed by Abeta(1)(-)(40). The kinetics of fibrillogenesis, however, occur without the typical lag period, and at a rate approximately 1000-fold greater than is seen with Abeta(1)(-)(40) fibrillogenesis. The strong tendency toward self-association is also shown by size exclusion chromatography in which Abeta(1)(-)(40)-Lactam(D23/K28) forms oligomers even at concentrations of approximately 1-5 microM. Under the same conditions, Abeta(1)(-)(40) shows no detectable oligomers by size exclusion chromatography. Our data suggest that Abeta(1)(-)(40)-Lactam(D23/K28) could bypass an unfavorable folding step in fibrillogenesis, because the lactam linkage "preforms" a bendlike structure in the peptide. Consistent with this view Abeta(1)(-)(40) growth is efficiently nucleated by Abeta(1)(-)(40)-Lactam(D23/K28) fibril seeds.