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State Medicaid programs cover nearly all Food and Drug Administration-approved prescription drugs in exchange for mandatory manufacturer rebates, including rebates that offset price increases beyond inflation. These inflationary rebates originally applied to brand-name drugs only, but in 2017 Congress expanded them to include generics. Using public Medicaid medication spending and utilization data and three different measures of drug prices, we found that nearly half of generic drugs were subject to inflationary rebates during the period 2017-20, offsetting 2-12 percent of the $53.6 billion in generic drug spending during that time. Rebates were larger among non-orally administered drugs and those with the highest prices. Generic inflationary rebates offset substantial Medicaid spending during that period, suggesting that many generic prices increased above inflation despite the new policy. This might change now that inflationary rebates have been expanded to Medicare under the Inflation Reduction Act of 2022, although additional policies that ensure competitive markets would better protect all US patients from rising generic drug prices.

Although generic drugs are typically inexpensive, rising prices among some generic drugs in recent years have raised concern. Using Medicaid data, we found that one in five generic drugs sold in the US experienced a price spike (defined as a doubling in price over the course of one year) initiated by at least one manufacturer during the period 2014–17. There was a trend toward fewer price spikes each year, from 7.8 percent of drugs in 2014 to 5.8 percent in 2017. Among drugs experiencing price spikes, 51 percent were injected products, 64 percent had three or fewer manufacturers, and 18 percent were in shortage at the time of the spike. Generic drug price spikes cost Medicaid $1.5 billion during 2014–16, representing 4.2 percent of all Medicaid generic drug spending in that period. The trend toward fewer price spikes over time may be due to increased public scrutiny and regulatory actions. However, price spikes can be very costly, and additional policies are needed to both ensure adequate competition and control prices among generic drugs.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that causes compromised function of motor neurons and neuronal death. However, oculomotor neurons are largely spared from disease symptoms. The underlying causes for sporadic ALS as well as for the resistance of oculomotor neurons to disease symptoms remain poorly understood. In this bioinformatic-analysis, we compared the gene expression profiles of spinal and oculomotor tissue samples from control individuals and sporadic ALS patients. We show that the genes GAD2 and GABRE (involved in GABA signaling), and CALB1 (involved in intracellular Ca2+ ion buffering) are downregulated in the spinal tissues of ALS patients, but their endogenous levels are higher in oculomotor tissues relative to the spinal tissues. Our results suggest that the downregulation of these genes and processes in spinal tissues are related to sporadic ALS disease progression and their upregulation in oculomotor neurons confer upon them resistance to ALS symptoms. These results build upon prevailing models of excitotoxicity that are relevant to sporadic ALS disease progression and point out unique opportunities for better understanding the progression of neurodegenerative properties associated with sporadic ALS.

Controlling gene expression and chromatin state via the recruitment of transcriptional effector proteins to specific genetic loci has advanced the potential of mammalian synthetic biology, but is still hindered by the challenge of delivering large chromatin regulators. Here, we develop a new method for generating small nanobodies against human chromatin regulators that can repress or activate gene expression. We start with a large and diverse nanobody library and perform enrichment against chromatin regulatory complexes using yeast display, followed by high-throughput pooled selection for transcriptional control when recruited to a reporter in human cells. This workflow allows us to efficiently select tens of functional nanobodies that can act as transcriptional repressors or activators in human cells.

In the trauma resuscitation literature, there are inconsistent definitions of what constitutes massive transfusion and a unit of blood, complicating the use of transfusion cut-points to declare futility. This is problematic as it can lead to the inefficient use of blood products, further exacerbating current blood product shortages. Previous studies have used various transfusion cut-points per hour to define futility in retrospective analyses but have not accurately defined futility at the bedside due to patient survival even at large rates and volumes of blood transfused. In an attempt to use transfusion cut-points as a marker to help define futility, guidelines have been proposed to limit blood product waste in transfusions for severely bleeding trauma patients, such as Suspension of Transfusion and Other Procedures (STOP) for patients older than 15 and the Futility of Resuscitation Measure (FoRM), used to determine futility in patients older than 60. In an effort to construct effective bedside futile resuscitation criteria with 100% positive predictive value and specificity, this review proposes the use of specific blood component transfusion cut-points combined with parameters from both STOP and FoRM to allow for a comprehensive and accurate method of declaring futility in severely bleeding trauma patients.