Blood product use for radiological/nuclear trauma: product development and US regulatory considerations.

Blood products are likely to be critical components of the medical response to nuclear detonation, as the hematopoietic subsyndrome of acute radiation syndrome (H-ARS) includes depletion of platelets and red blood cells that can lead to lethal hemorrhage and anemia. There is, however, only limited clinical information on the use of blood products to treat H-ARS. As currently configured, the US blood supply cannot meet the predicted surge in blood product demand that is likely to occur short-term and possibly long-term in the event of a large nuclear detonation. As part of the Administration for Strategic Preparedness and Response within the US Department of Health and Human Services, the Biomedical Advanced Research and Development Authority (BARDA) is addressing this preparedness gap by supporting the development of novel blood products and devices with characteristics that improve blood product storage and use in austere operational environments. The US Food and Drug Administration's Center for Drug Evaluation and Research (CDER) recently issued draft guidance on the development of drugs and biologics regulated by CDER to prevent or treat Acute Radiation Syndrome under the provisions of the "Animal Rule." The commentary provided here discusses the unique regulatory scheme for transfusion components and blood products regulated as biological drugs by Center for Biologics Evaluation and Research, including the ambiguity surrounding the evidentiary requirements for their approval for H-ARS, and whether, under certain circumstances, a specific H-ARS indication is necessary if relevant commercial indications are approved.

Racial and Ethnic Disparities in Outpatient Treatment of COVID-19 - United States, January-July 2022.

In December 2021 and early 2022, four medications received emergency use authorization (EUA) by the Food and Drug Administration for outpatient treatment of mild-to-moderate COVID-19 in patients who are at high risk for progressing to severe disease; these included nirmatrelvir/ritonavir (Paxlovid) and molnupiravir (Lagevrio) (both oral antivirals), expanded use of remdesivir (Veklury; an intraveneous antiviral), and bebtelovimab (a monoclonal antibody [mAb]).* Reports have documented disparities in mAb treatment by race and ethnicity (1) and in oral antiviral treatment by zip code-level social vulnerability (2); however, limited data are available on racial and ethnic disparities in oral antiviral treatment.† Using electronic health record (EHR) data from 692,570 COVID-19 patients aged ≥20 years who sought medical care during January-July 2022, treatment with Paxlovid, Lagevrio, Veklury, and mAbs was assessed by race and ethnicity, overall and among high-risk patient groups. During 2022, the percentage of COVID-19 patients seeking medical care who were treated with Paxlovid increased from 0.6% in January to 20.2% in April and 34.3% in July; the other three medications were used less frequently (0.7%-5.0% in July). During April-July 2022, when Paxlovid use was highest, compared with White patients, Black or African American (Black) patients were prescribed Paxlovid 35.8% less often, multiple or other race patients 24.9% less often, American Indian or Alaska Native and Native Hawaiian or other Pacific Islander (AIAN/NHOPI) patients 23.1% less often, and Asian patients 19.4% less often; Hispanic patients were prescribed Paxlovid 29.9% less often than non-Hispanic patients. Racial and ethnic disparities in Paxlovid treatment were generally somewhat higher among patients at high risk for severe COVID-19, including those aged ≥50 years and those who were immunocompromised. The expansion of programs focused on equitable awareness of and access to outpatient COVID-19 treatments, as well as COVID-19 vaccination, including updated bivalent booster doses, can help protect persons most at risk for severe illness and facilitate equitable health outcomes.

Evidence for angiogenesis in Parkinson's disease, incidental Lewy body disease, and progressive supranuclear palsy.

Angiogenesis has not been extensively studied in Parkinson's disease (PD) despite being associated with other neurodegenerative disorders. Post-mortem human brain tissues were obtained from subjects with pathologically confirmed Parkinson's disease (PD) and progressive supranuclear palsy (PSP), a rapidly progressing Parkinsonian-like disorder. Tissues were also obtained from subjects with incidental Lewy body disease (iLBD) who had Lewy bodies in the substantia nigra pars compacta (SN(pc)) but had not been diagnosed with PD, and age-matched controls without Lewy body pathology. The SNpc, putamen, locus ceruleus (LC) and midfrontal cortex were examined for integrin αvß3, a marker for angiogenesis, along with vessel number and activated microglia. All parkinsonian syndromes had greater αvß3 in the LC and the SN(pc), while only PD and PSP subjects had elevated αvß3 in the putamen compared to controls. PD and PSP subjects also had increases in microglia number and activation in the SN(pc) suggesting a link between inflammation and clinical disease. Microglia activation in iLBD subjects was limited to the LC, an area involved at an early stage of PD. Likewise, iLBD subjects did not differ from controls in αvß3 staining in the putamen, a late area of involvement in PD. The presence of αvß3 reactive vessels in PD and its syndromes is indicative of newly created vessels that have not likely developed the restrictive properties of the blood brain barrier. Such angiogenic vessels could contribute to neuroinflammation by failing to protect the parenchyma from peripheral immune cells and inflammatory or toxic factors in the peripheral circulation.

An angiogenic inhibitor, cyclic RGDfV, attenuates MPTP-induced dopamine neuron toxicity.

We previously demonstrated that several dopamine (DA) neurotoxins produced punctate areas of FITC-labeled albumin (FITC-LA) leakage in the substantia nigra and striatum suggesting blood brain barrier (BBB) dysfunction. Further, this leakage was co-localized with αvß3 integrin up-regulation, a marker for angiogenesis. This suggested that the FITC-LA leakage might have been a result of angiogenesis. To assess the possible role of angiogenesis in DA neuron loss, we treated mice with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and on the following day treated with cyRGDfV, a cyclic peptide that binds to integrin αvß3 and prevents angiogenesis. Post-treatment for 3 days (b.i.d.) with cyRGDfV blocked the MPTP-induced upregulation of integrin ß3 immunoreactivity (a marker for angiogenesis), leakage of FITC-LA into brain parenchyma (a marker for BBB disruption) as well as the down regulation of Zona Occludin-1 (ZO-1; a marker for tight junction integrity). In addition, cyRGDfV also completely prevented tyrosine hydroxylase immunoreactive cell loss (a marker for DA neurons) and markedly attenuated the up-regulation of activated microglia (Iba1 cell counts and morphology). These data suggest that cyRGDfV, and perhaps other anti-angiogenic drugs, are neuroprotective following acute MPTP treatment and may suggest that compensatory angiogenesis and BBB dysfunction may contribute to inflammation and DA neuron loss.