Prevalence of Medical Payment Products Promoted on US Hospitals' Websites.

This cross-sectional study examines the prevalence of hospital-promoted medical payment products (MPPs) by whether hospitals offered any MPP or an interest-bearing MPP.

Vaccine value profile for Klebsiella pneumoniae.

Klebsiella pneumoniae causes community- and healthcare-associated infections in children and adults. Globally in 2019, an estimated 1.27 million (95% Uncertainty Interval [UI]: 0.91-1.71) and 4.95 million (95% UI: 3.62-6.57) deaths were attributed to and associated with bacterial antimicrobial resistance (AMR), respectively. K. pneumoniae was the second leading pathogen in deaths attributed to AMR resistant bacteria. Furthermore, the rise of antimicrobial resistance in both community- and hospital-acquired infections is a concern for neonates and infants who are at high risk for invasive bacterial disease. There is a limited antibiotic pipeline for new antibiotics to treat multidrug resistant infections, and vaccines targeted against K. pneumoniae are considered to be of priority by the World Health Organization. Vaccination of pregnant women against K. pneumoniae could reduce the risk of invasive K.pneumoniae disease in their young offspring. In addition, vulnerable children, adolescents and adult populations at risk of K. pneumoniae disease with underlying diseases such as immunosuppression from underlying hematologic malignancy, chemotherapy, patients undergoing abdominal and/or urinary surgical procedures, or prolonged intensive care management are also potential target groups for a K. pneumoniae vaccine. A 'Vaccine Value Profile' (VVP) for K.pneumoniae, which contemplates vaccination of pregnant women to protect their babies from birth through to at least three months of age and other high-risk populations, provides a high-level, holistic assessment of the available information to inform the potential public health, economic and societal value of a pipeline of K. pneumoniae vaccines and other preventatives and therapeutics. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public-private partnerships, and multi-lateral organizations, and in collaboration with stakeholders from the WHO. All contributors have extensive expertise on various elements of the K.pneumoniae VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

Commercial Payments for COVID-19-Associated Inpatient Stays in 2020.

This cross-sectional study reports the allowed reimbursement amounts for inpatient COVID-19 care for different types of hospitals.

Repeated seizures lead to progressive ventilatory dysfunction in SSKcnj16-/- rats.

Patients with uncontrolled epilepsy experience repeated seizures putting them at increased risk for sudden unexpected death in epilepsy (SUDEP). Data from human patients have led to the hypothesis that SUDEP results from severe cardiorespiratory suppression after a seizure, which may involve pathological deficiencies in the brainstem serotonin (5-HT) system. Rats with a genomic Kcnj16 mutation (SSKcnj16-/- rats) are susceptible to sound-induced generalized tonic-clonic seizures (GTCS) which, when repeated once daily for up to 10 days (10-day seizure protocol), increased mortality, particularly in male rats. Here, we test the hypothesis that repeated seizures across the 10-day protocol will cause a progressive ventilatory dysfunction due to time-dependent 5-HT deficiency. Initial severe seizures led to ictal and postictal apneas and transient decreases in breathing frequency, ventilatory drive, breath-to-breath variability, and brief hypoventilation. These seizure-induced effects on ventilation were exacerbated with increasing seizures and ventilatory chemoreflexes became further impaired after repeated seizures. Tissue analyses of key brainstem regions controlling breathing showed time-dependent 5-HT system suppression and increased immunoreactivity for IBA-1 (microglial marker) without changes in overall cell counts at 3, 7, and 10 days of seizures. Fluoxetine treatment in SSKcnj16-/- rats prevented repeated seizure-induced progressive respiratory suppression but failed to prevent seizure-related mortality. We conclude that repeated seizures cause a progressive compromise of ventilatory control in the immediate postictal period largely mediated by serotonin system suppression in brainstem regions of respiratory control. However, other unknown factors contribute to overall survival following repeated seizures in this model.NEW & NOTEWORTHY This study demonstrated that repeated seizures in a novel rat model (SSKcnj16-/- rats) caused a progressively greater ventilatory dysfunction in the immediate postictal period associated with brainstem serotonin (5-HT) suppression. Augmenting brain 5-HT with a selective serotonin reuptake inhibitor prevented the progressive ventilatory dysfunction induced by repeated seizures but failed to prevent seizure-related mortality, suggesting that repeated seizures may lead to cardiorespiratory suppression and failure through multiple mechanisms.

A NPAS4-NuA4 complex couples synaptic activity to DNA repair.

Neuronal activity is crucial for adaptive circuit remodelling but poses an inherent risk to the stability of the genome across the long lifespan of postmitotic neurons1-5. Whether neurons have acquired specialized genome protection mechanisms that enable them to withstand decades of potentially damaging stimuli during periods of heightened activity is unknown. Here we identify an activity-dependent DNA repair mechanism in which a new form of the NuA4-TIP60 chromatin modifier assembles in activated neurons around the inducible, neuronal-specific transcription factor NPAS4. We purify this complex from the brain and demonstrate its functions in eliciting activity-dependent changes to neuronal transcriptomes and circuitry. By characterizing the landscape of activity-induced DNA double-strand breaks in the brain, we show that NPAS4-NuA4 binds to recurrently damaged regulatory elements and recruits additional DNA repair machinery to stimulate their repair. Gene regulatory elements bound by NPAS4-NuA4 are partially protected against age-dependent accumulation of somatic mutations. Impaired NPAS4-NuA4 signalling leads to a cascade of cellular defects, including dysregulated activity-dependent transcriptional responses, loss of control over neuronal inhibition and genome instability, which all culminate to reduce organismal lifespan. In addition, mutations in several components of the NuA4 complex are reported to lead to neurodevelopmental and autism spectrum disorders. Together, these findings identify a neuronal-specific complex that couples neuronal activity directly to genome preservation, the disruption of which may contribute to developmental disorders, neurodegeneration and ageing.

Ground Ambulance Billing And Prices Differ By Ownership Structure.

The No Surprises Act prohibits most surprise billing but notably does not apply to ground ambulance services. In this study we created a novel data set that identifies the ownership structure of ground ambulance organizations to compare pricing and billing between private- and public-sector ambulances, with a specific focus on organizations owned by private equity or publicly traded companies. Overall, we found that 28 percent of commercially insured emergency ground ambulance transports during the period 2014-17 resulted in a potential surprise bill. Our analysis illustrates that being transported by a private-sector ambulance in an emergency comes with substantially higher allowed amounts, patient cost sharing, and potential surprise bills compared with being transported by a public-sector ambulance. Further, allowed amounts and cost sharing tended to be higher for private equity- or publicly traded company-owned ambulances than other private-sector ambulances. These findings highlight substantial patient liability and important differences in pricing and billing patterns between public- and private-sector ground ambulance organizations.

Comparison of Estimated No Surprises Act Qualifying Payment Amounts and Payments to In-Network and Out-of-Network Emergency Medicine Professionals.

Importance: The No Surprises Act (NSA), which took effect on January 1, 2022, applies a qualifying payment amount (QPA) as an out-of-network payment reference point. An understanding of how QPA measures compare with the in-network and out-of-network payments physicians received before the NSA implementation may be useful to policy makers and stakeholders. Objective: To estimate the QPA for geographic and funding markets and compare QPA estimates with in-network and out-of-network payments for 2019 emergency medicine claims. Design, Setting, and Participants: This cross-sectional study of US commercial insurance claims assessed the Health Care Cost Institute's 2019 commercial professional emergency medicine claims (Current Procedural Terminology [CPT] codes 99281-99285 and 99291) and included enrollees in commercial health maintenance organizations, exclusive provider organizations, point of service, and preferred provider organizations self-funded and fully insured through Aetna, Humana, and some Blue Health Intelligence plans. Claims with missing or inconsistent data fields were excluded. Data were analyzed November 1, 2021, to April 7, 2022. Main Outcomes and Measures: The QPA was calculated as the median allowed amount of all observed claims within strata defined by geographic region, CPT code, and funding market. For each stratum, the ratio of mean in-network allowed amounts to QPAs and mean out-of-network allowed amounts to QPAs were calculated. Then the volume-weighted mean of these ratios was computed across CPT codes within each geographic and funding market stratum. Results: The analytic sample included 7 556 541 professional emergency claims with a mean (SD) allowed amount of $313 ($306) and mean (SD) QPA of $252 ($133). Among the 650 geographic and market strata in the sample, the mean in-network allowed amounts were 14% (ratio, 0.96) higher than the estimated QPA. For the subset of strata with a sufficient sample of out-of-network claims (n = 227), the mean out-of-network payments were 112% (ratio, 2.12) higher than the QPA. More generous out-of-network payments were from self-funded plans (120% [ratio, 2.20] higher than the QPA estimate) vs fully insured plans (43% [ratio, 1.43] higher than the QPA estimate). Mean in-network allowed amounts for nonphysician clinicians were 4% (ratio, 1.04) lower than the QPA, whereas mean in-network allowed amounts for physicians were 15% (ratio, 1.15) higher than the QPA estimates. These differences remained after adjusting for geographic region. Conclusions and Relevance: The findings of this cross-sectional study of US commercial insurance claims suggest that the NSA may have heterogeneous implications for out-of-network payments and negotiating leverage experienced by emergency medicine physicians in different geographic markets, with the potential for greater implications in the self-funded market.

Developmental dynamics of RNA translation in the human brain.

The precise regulation of gene expression is fundamental to neurodevelopment, plasticity and cognitive function. Although several studies have profiled transcription in the developing human brain, there is a gap in understanding of accompanying translational regulation. In this study, we performed ribosome profiling on 73 human prenatal and adult cortex samples. We characterized the translational regulation of annotated open reading frames (ORFs) and identified thousands of previously unknown translation events, including small ORFs that give rise to human-specific and/or brain-specific microproteins, many of which we independently verified using proteomics. Ribosome profiling in stem-cell-derived human neuronal cultures corroborated these findings and revealed that several neuronal activity-induced non-coding RNAs encode previously undescribed microproteins. Physicochemical analysis of brain microproteins identified a class of proteins that contain arginine-glycine-glycine (RGG) repeats and, thus, may be regulators of RNA metabolism. This resource expands the known translational landscape of the human brain and illuminates previously unknown brain-specific protein products.

Insurers negotiate lower hospital prices for HIX than for commercial groups.

OBJECTIVES: This study investigates a sample of the pricing data released by hospitals under the price transparency law effective January 2021 to better understand the prices paid by health insurance exchange (HIX) plans relative to commercial group and Medicare Advantage plans. STUDY DESIGN: Cross-sectional analysis of hospital pricing data. METHODS: We compared allowed amounts for 25 common inpatient services and 56 common outpatient services across 22 hospital-insurer dyads, selected by the availability of plan-specific pricing data from the top 100 hospitals by bed counts and the top 100 hospitals by gross revenue based on 2017 CMS data. RESULTS: Insurers in our sample generally negotiated allowed amounts for their HIX plans that were lower than their commercial group rates and well above their Medicare Advantage contracts within the same hospital. CONCLUSIONS: Allowed amounts for HIX plans were generally lower than commercial group rates and higher than Medicare Advantage rates. Better information on HIX pricing is needed as the federal government and states consider additional ways to expand health care coverage, such as public options or expanded Medicaid or Medicare eligibility.

Physician Compensation Arrangements and Financial Performance Incentives in US Health Systems.

Importance: Public and private payers continue to expand use of alternative payment models, aiming to use value-based payment to affect the care delivery of their contracted health system partners. In parallel, health systems and their employment of physicians continue to grow. However, the degree to which health system physician compensation reflects an orientation toward value, rather than volume, is unknown. Objective: To characterize primary care physician (PCP) and specialist compensation arrangements among US health system-affiliated physician organizations (POs) and measure the portion of total physician compensation based on quality and cost performance. Design Setting and Participants: This study was a cross-sectional mixed-methods analysis of in-depth multimodal data (compensation document review, interviews with 40 PO leaders, and surveys conducted between November 2017 and July 2019) from 31 POs affiliated with 22 purposefully selected health systems in 4 states. Data were analyzed from June 2019 to September 2020. Main Outcomes and Measures: The frequency of PCP and specialist compensation types and the percentage of compensation when included, including base compensation incentives, quality and cost performance incentives, and other financial incentives. The top 3 actions physicians could take to increase their compensation. The association between POs' percentage of revenue from fee-for-service and their physicians' volume-based compensation percentage. Results: Volume-based compensation was the most common base compensation incentive component for PCPs (26 POs [83.9%]; mean, 68.2% of compensation; median, 81.4%; range, 5.0%-100.0% when included) and specialists (29 POs [93.3%]; mean, 73.7% of compensation; median, 90.5%; range, 2.5%-100.0% when included). While quality and cost performance incentives were common (included by 83.9%-56.7% of POs for PCPs and specialists, respectively), the percentage of compensation based on quality and cost performance was modest (mean, 9.0% [median, 8.3%; range, 1.0%-25.0%] for PCPs and 5.3% [median, 4.5%; range, 0.5%-16.0%] for specialists when included). Increasing the volume of services was the most commonly cited action for physicians to increase compensation, reported as the top action by 22 POs (70.0%) for PCPs and specialists. We observed a very weak, nonsignificant association between the percentage of revenue of POs from fee for service and the PCP and specialist volume-based compensation percentage (r = 0.08; P = .78 and r = -0.04; P = .89, respectively). Conclusions and Relevance: The results of this cross-sectional study suggest that PCPs and specialists despite receiving value-based reimbursement incentives from payers, the compensation of health system PCPs and specialists was dominated by volume-based incentives designed to maximize health systems revenue.

Medicare Advantage Plans Pay Large Markups To Consolidated Dialysis Organizations.

The 21st Century Cures Act of 2016 lifted regulations prohibiting Medicare Advantage (MA) enrollment after patients initiate dialysis, starting in 2021, and early reports indicate increased MA enrollment among such patients. Large shifts into Medicare Advantage could disrupt the market because the consolidated dialysis industry can negotiate payment from MA plans that is higher than that for fee-for-service Medicare. For three large insurers representing 48 percent of the 2016-17 MA market, we found that MA plans paid 27 percent more than fee-for-service Medicare. Larger dialysis center chains commanded higher markups. Virtually all facilities of the two largest chains were in network, suggesting that they leverage their market power into all-or-nothing negotiations with plans. Policy makers should consider regulations that limit market consolidation among dialysis providers, as well as their ability to exercise that power in the MA market.

Patch-to-Seq and Transcriptomic Analyses Yield Molecular Markers of Functionally Distinct Brainstem Serotonin Neurons.

Acute regulation of CO2 and pH homeostasis requires sensory feedback from peripheral (carotid body) and central (central) CO2/pH sensitive cells - so called respiratory chemoreceptors. Subsets of brainstem serotonin (5-HT) neurons in the medullary raphe are CO2 sensitive or insensitive based on differences in embryonic origin, suggesting these functionally distinct subpopulations may have unique transcriptional profiles. Here, we used Patch-to-Seq to determine if the CO2 responses in brainstem 5-HT neurons could be correlated to unique transcriptional profiles and/or unique molecular markers and pathways. First, firing rate changes with hypercapnic acidosis were measured in fluorescently labeled 5-HT neurons in acute brainstem slices from transgenic, Dahl SS (SSMcwi) rats expressing T2/ePet-eGFP transgene in Pet-1 expressing (serotonin) neurons (SS ePet1-eGFP rats). Subsequently, the transcriptomic and pathway profiles of CO2 sensitive and insensitive 5-HT neurons were determined and compared by single cell RNA (scRNAseq) and bioinformatic analyses. Low baseline firing rates were a distinguishing feature of CO2 sensitive 5-HT neurons. scRNAseq of these recorded neurons revealed 166 differentially expressed genes among CO2 sensitive and insensitive 5-HT neurons. Pathway analyses yielded novel predicted upstream regulators, including the transcription factor Egr2 and Leptin. Additional bioinformatic analyses identified 6 candidate gene markers of CO2 sensitive 5-HT neurons, and 2 selected candidate genes (CD46 and Iba57) were both expressed in 5-HT neurons determined via in situ mRNA hybridization. Together, these data provide novel insights into the transcriptional control of cellular chemoreception and provide unbiased candidate gene markers of CO2 sensitive 5-HT neurons. Methodologically, these data highlight the utility of the patch-to-seq technique in enabling the linkage of gene expression to specific functions, like CO2 chemoreception, in a single cell to identify potential mechanisms underlying functional differences in otherwise similar cell types.

The CARB-X Portfolio of Nontraditional Antibacterial Products.

The growing prevalence of antibiotic-resistant bacterial pathogens and the lack of new medicines to treat the infections they cause remain a significant global threat. In recent years, this ongoing unmet need has encouraged more research groups to focus on the discovery and development of nontraditional antibacterial agents, ranging from anti-virulence strategies to bacteriophage and ways to modulate the microbiome. The Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) is a global nonprofit public-private partnership dedicated to accelerating antibacterial-related research. Importantly, the CARB-X portfolio supports a wide variety of novel and innovative nontraditional programs to help the global antibacterial research ecosystem understand the potential that these modalities can play in the management or prevention of serious infections. We describe here the breadth of the CARB-X pipeline of novel nontraditional products.

Efficacy of Delafloxacin against the Biothreat Pathogen Burkholderia pseudomallei.

The in vitro activity and in vivo efficacy of delafloxacin were evaluated against the causative pathogen of melioidosis, Burkholderia pseudomallei. Delafloxacin MICs were determined by broth microdilution according to CLSI guidelines for 30 isolates of B. pseudomallei. The in vivo efficacy of delafloxacin was studied at a range of doses in a postexposure prophylaxis (PEP) murine model of melioidosis. Delafloxacin was active in vitro against B. pseudomallei (MIC90, 1 µg/ml). When the mice were dosed with 50 mg/kg body weight and 80 mg/kg body weight delafloxacin at both 16 and 24 h, greater survival was observed (90% to 100% survival) than with the 30-mg/kg-dosed mice (70% survival). All delafloxacin-treated cohorts contained no detectable B. pseudomallei in the spleens at the end of the study. This contrasts with ceftazidime 16- and 24-h administration, which had 40% and 20% survival, respectively. Complete clearance of infection was observed for most but not all surviving cohorts administered ceftazidime. In the mouse model of infection, survival curves for delafloxacin- and ceftazidime-treated animals at treatment start times of 16 and 24 h were statistically significant (P values of <0.0001). Estimated daily delafloxacin exposures in the B. pseudomallei murine aerosol study were similar to daily human exposures with the approved twice a day (BID) intravenous (i.v.) (300 mg) or oral (450 mg) dosing regimens. Based on its in vitro and in vivo activity, its safety, and its tolerability profile, delafloxacin may offer an attractive treatment option as PEP or eradication therapy for B. pseudomallei. Evaluation in other in vivo infection models for B. pseudomallei should be considered.

Congress ends surprise billing: implications for payers, providers, and patients.

Compromise over ending surprise billing had consistently hit a deadlock as providers, payers, and patient groups found themselves at odds over mechanisms to resolve payment. The COVID-19 pandemic, however, accelerated legislative action on health care proposals, leading to the last-minute passage of the No Surprises Act at the end of 2020. The law marks a rare bipartisan success that promises to secure patient protections while also adding price transparency tools. Importantly, it creates an independent dispute resolution process that balances the demands of payers and providers in negotiating surprise billing. While the cost implications of this process will not be known until after implementation in 2022, it creates a template for states to emulate. Furthermore, it will reorient the relationships among payers and provider groups that have historically relied on out-of-network billing. This new competitive reality is an important step for consumer financial protection in health care.

Commercial and Medicare Advantage payment for anesthesiology services.

OBJECTIVES: Anesthesiology services are a focal point of policy making to address surprise medical billing. However, allowed amounts and charges for anesthesiology services have been understudied due to the specialty's unique conversion factor (CF) unit of payment and complex provider structures involving anesthesiologists and certified registered nurse anesthetists (CRNAs). This study compares payments for common outpatient anesthesiology services by commercial health plans, Medicare Advantage (MA), and traditional Medicare. STUDY DESIGN: Analysis of 2016-2017 claims from Health Care Cost Institute. METHODS: We derived allowed amount and charge CFs for commercial and MA claims using the base units assigned to each procedure code, time units, and modifiers. We computed the ratio of the allowed amount and charge CFs relative to the traditional Medicare CF. We described these payment measures by provider structure and network status. RESULTS: Mean in-network commercial allowed amount CFs for anesthesiology services ($70) are 314% of the traditional Medicare rate ($22), whereas mean commercial charge CFs ($148) are 659% of the Medicare rate. Commercial payments vary widely and are higher to anesthesiologists than to CRNAs and higher out of network than in network. MA plan payments align with traditional Medicare with payment parity between anesthesiologists and CRNAs, both in network and out of network. CONCLUSIONS: Common payment measures for anesthesia services-commercial allowed amounts, charges, or traditional Medicare-are highly divergent. MA plans' relatively low payments likely reflect the cost-containing influence of competition with traditional Medicare and MA's prohibition on balance billing. Out-of-network benchmarks for anesthesia services, such as the "qualifying payment amount" used in the No Surprises Act as a guidepost for arbitrators, may benefit from considering commercial payment differences across independent anesthesiologist, independent CRNA, or anesthesiologist-CRNA dyad provider structures.

Arbitration Over Out-Of-Network Medical Bills: Evidence From New Jersey Payment Disputes.

In 2018 New Jersey implemented a final-offer arbitration system to resolve payment disputes between insurers and out-of-network providers over surprise medical bills. Similar proposals are being considered by Congress and other states. In this article we examine how arbitration decisions compare with other relevant provider payment amounts by linking administrative data from New Jersey arbitration cases to Medicare and commercial insurance claims data. We find that decisions track closely with one of the metrics that arbitrators are shown-the eightieth percentile of provider charges-with the median decision being 5.7 times prevailing in-network rates for the same services. It is not a foregone conclusion that arbitrators will select winning offers based on proximity to this target, although our findings suggest that it is a strong anchor. The amount that providers can expect to receive through the arbitration process also affects their bargaining leverage with insurers, which could affect in-network negotiated rates more broadly. Therefore, basing arbitration decisions or a payment standard on unilaterally set provider-billed charges appears likely to increase health care costs relative to other surprise billing solutions and perversely incentivizes providers to inflate their charges over time.

Maternal immune activation in mice disrupts proteostasis in the fetal brain.

Maternal infection and inflammation during pregnancy are associated with neurodevelopmental disorders in offspring, but little is understood about the molecular mechanisms underlying this epidemiologic phenomenon. Here, we leveraged single-cell RNA sequencing to profile transcriptional changes in the mouse fetal brain in response to maternal immune activation (MIA) and identified perturbations in cellular pathways associated with mRNA translation, ribosome biogenesis and stress signaling. We found that MIA activates the integrated stress response (ISR) in male, but not female, MIA offspring in an interleukin-17a-dependent manner, which reduced global mRNA translation and altered nascent proteome synthesis. Moreover, blockade of ISR activation prevented the behavioral abnormalities as well as increased cortical neural activity in MIA male offspring. Our data suggest that sex-specific activation of the ISR leads to maternal inflammation-associated neurodevelopmental disorders.