USAFSAM Aeromedical Consultation Service Medical Risk Assessment and Airworthiness Matrix.

INTRODUCTION: The 1% rule has long been a standard threshold for aerospace medical risk acceptance, but medical literature has noted multiple shortcomings with this threshold. Previous studies have suggested a risk matrix approach in aeromedical decision-making. General use of risk matrices for risk assessment is already codified in the U.S. Air Force (USAF). Based on this, the USAF School of Aerospace Medicine (USAFSAM) Aeromedical Consultation Service (ACS) generated and evaluated the ACS Medical Risk Assessment and Airworthiness Matrix (AMRAAM).METHODS: The ACS adapted existing USAF standards to build the AMRAAM, gathered expert feedback, and sampled 100 previously adjudicated cases to compare legacy case dispositions to AMRAAM dispositions using polychoric correlation.RESULTS: The AMRAAM disposition showed strong agreement with legacy dispositions (ρ* = 0.9424). One case was discarded as it did not meet inclusion criteria. Of the 99 remaining cases, 88 had perfect agreement between legacy and AMRAAM dispositions. With the AMRAAM, eight cases were less restrictive and three were more restrictive (two due to an erroneous omission in the legacy disposition).DISCUSSION: The AMRAAM produces disposition recommendations that are highly consistent with the legacy approach informed by the 1% rule, with discordant AMRAAM dispositions tending to be more permissive. The USAFSAM AMRAAM allows a more dimensional risk evaluation than the 1% rule, communicates aeromedical risk consistent with nonmedical USAF organizations, and harmonizes aeromedical risk with the level of risk the USAF has defined for all flying systems. The ACS will use the AMRAAM as standard practice in future aeromedical risk assessments.Mayes RS, Keirns CJ, Hicks AG, Menner LD, Lee MS, Wagner JH, Baltzer RL. USAFSAM Aeromedical Consultation Service Medical Risk Assessment and Airworthiness Matrix. Aerosp Med Hum Perform. 2023; 94(7):514-522.

Cell Culture Process Scale-Up Challenges for Commercial-Scale Manufacturing of Allogeneic Pluripotent Stem Cell Products.

Allogeneic cell therapy products, such as therapeutic cells derived from pluripotent stem cells (PSCs), have amazing potential to treat a wide variety of diseases and vast numbers of patients globally. However, there are various challenges related to manufacturing PSCs in single-use bioreactors, particularly at larger volumetric scales. This manuscript addresses these challenges and presents potential solutions to alleviate the anticipated bottlenecks for commercial-scale manufacturing of high-quality therapeutic cells derived from PSCs.

Exercise Effects on Neck Function Among F-15E Aircrew.

BACKGROUND: Neck pain (NP) is common among high performance aircrew, yet evidence remains insufficient to guide examination, treatment, and prevention. The purpose of this randomized pilot study was to collect baseline data for neck function for F-15E aircrew and determine efficacy and feasibility of two separate exercise protocols in measuring short-term outcomes of subjective and objective neck function in order to inform future study design. METHODS: Randomized to either progressive (PRO) or general (GEN) exercise groups were 41 F-15E aircrew. Data collection occurred at baseline, 3 wk, and 3 mo. RESULTS: At baseline, 39% of the subjects reported current NP, 79.5% reported a history of NP attributed to flying, 12.8% reported being removed from flying duties due to NP, and 10% reported receiving medical care for NP. PRO and GEN group randomization showed similar baseline assessment data. Blinding was successful and exercise logs showed 31.6% compliance with prescribed exercise regimens. There were small but statistically significant increases in neck range of motion in both groups over the course of the study. Aircrew with current NP had significantly higher F-15E flight hours. DISCUSSION: This study supports the high prevalence of NP in aircrew, yet low frequency of seeking care for NP. Future studies to assess NP prevention and treatment in aircrew require an integrated approach that includes operational exercise policy and long-term data collection in flying units with dedicated resources for assessment and analysis. Lee MS, Briggs R, Scheirer V, Kearby G, Young BA. Exercise effects on neck function among F-15E aircrew. Aerosp Med Hum Perform. 2021; 92(10):815824.

Diabetes mellitus increases the risk of mortality following liver transplantation independent of MELD score.

BACKGROUND: Patients with diabetes mellitus overall experience worse health outcomes than non-diabetics, but whether this is true among recipients of liver transplantation still remains unclear. The aim of this study was to compare the mortality of diabetic and non-diabetic patients following liver transplantation. METHODS: We conducted a retrospective analysis of 530 adult patients undergoing liver transplantation at Stanford University Medical Center from February 1995 to July 2006. Information on diabetes mellitus was available for 431 patients; 96 patients who had acute liver failure (n = 17), combined liver and kidney transplantation (n = 28), or died prior to discharge (n = 51) were excluded from analysis. RESULTS: Over a mean follow-up of 4.5 years, survival was 81% in the diabetic group and 94% among controls (p = <0.0001). After controlling for age (mean +/- SD: 54.4 +/- 7.6 in diabetics, 50.1 +/- 9.6 in controls), body mass index (28.6 +/- 6.6 in diabetics, 27.1 +/- 5.4 in controls), presence of hepatitis C, and MELD score (17 +/- 9.6 in diabetics, 19 +/- 10.2 in controls), diabetes mellitus remained a significant predictor of death (HR 3.11, p = 0.01). CONCLUSIONS: Diabetes mellitus is an independent risk factor for mortality following liver transplantation. Further investigation of this relationship should focus on the impact of more intensive pre- and post-liver transplantation glucose control, cardiovascular risk factor reduction, and the effects of accelerated atherosclerosis in the setting of immune suppression.

Microchip assays for screening monoclonal antibody product quality.

Microchip CE-SDS was evaluated as a high-throughput alternative to conventional CE-SDS for monitoring monoclonal antibody protein quality. A commercial instrument (LabChip) 90) was used to separate dodecyl sulfate coated proteins through a sieving polymer based on the proteins' sizes. Under reducing conditions, the microchip CE-SDS separation was similar to that of conventional CE-SDS, providing reasonable resolution of the non-glycosylated and the glycosylated heavy chains. The fluorescence detection on LabChip 90 using non-covalent fluorescent labeling method was about as sensitive as the 220 nm UV detection used in a conventional CE instrument. A simple glycan typing assay was developed for the reducing microchip CE-SDS format. Antibodies, either pure or in crude cell culture media are treated with Endoglycosidase H, which specifically cleaves the hybrid and high mannose type glycans. A heavy chain migration shift on reducing CE-SDS resulting from the loss of glycan is used to measure the level of high mannose/hybrid type glycans as a percentage of the total glycans. Microchip CE-SDS, under both non-reducing and reducing conditions, can be used in a variety of antibody product screening assays. The microchip analyses provide sufficient resolution and sensitivity for this purpose but on a time scale approximately 70 times faster (41 s versus 50 min per sample) than conventional CE separation under typical operational conditions.

Acute myeloid leukemia in a patient with thrombocytopenia with absent radii: A case report and review of the literature.

Thrombocytopenia with absent radii (TAR) syndrome is a rare congenital disorder characterized by low platelet counts of various severity, bilateral absent radii but thumbs are usually present. TAR syndrome is not generally associated with bone marrow failure or malignancy. Janus kinase-2, myeloproliferative leukemia protein, and calreticulin are not mutated in TAR patients. Only four cases of leukemia were reported in TAR patients in the literature: three acute myeloid leukemia (AML) and one acute lymphoblastic leukemia. Of the three cases of AML found in TAR patient, only one was reported in an adult. We report a case of myelodysplastic syndrome progressing to AML with calreticulin driver mutation in an adult male with TAR syndrome who was successfully treated with hematopoietic allogeneic stem cell transplantation.

Sequence homology between HLA-bound cytomegalovirus and human peptides: A potential trigger for alloreactivity.

Human cytomegalovirus (hCMV) reactivation may often coincide with the development of graft-versus-host-disease (GVHD) in stem cell transplantation (SCT). Seventy seven SCT donor-recipient pairs (DRP) (HLA matched unrelated donor (MUD), n = 50; matched related donor (MRD), n = 27) underwent whole exome sequencing to identify single nucleotide polymorphisms (SNPs) generating alloreactive peptide libraries for each DRP (9-mer peptide-HLA complexes); Human CMV CROSS (Cross-Reactive Open Source Sequence) database was compiled from NCBI; HLA class I binding affinity for each DRPs HLA was calculated by NetMHCpan 2.8 and hCMV- derived 9-mers algorithmically compared to the alloreactive peptide-HLA complex libraries. Short consecutive (≥6) amino acid (AA) sequence homology matching hCMV to recipient peptides was considered for HLA-bound-peptide (IC50<500nM) cross reactivity. Of the 70,686 hCMV 9-mers contained within the hCMV CROSS database, an average of 29,658 matched the MRD DRP alloreactive peptides and 52,910 matched MUD DRP peptides (p<0.001). In silico analysis revealed multiple high affinity, immunogenic CMV-Human peptide matches (IC50<500 nM) expressed in GVHD-affected tissue-specific manner. hCMV+GVHD was found in 18 patients, 13 developing hCMV viremia before GVHD onset. Analysis of patients with GVHD identified potential cross reactive peptide expression within affected organs. We propose that hCMV peptide sequence homology with human alloreactive peptides may contribute to the pathophysiology of GVHD.

The Growing Public Health Challenges of Exposure to Ultraviolet Radiation From Use of Indoor Tanning Devices in the United States.

Ultraviolet radiation is recognized as a human carcinogen by the International Agency for Research on Cancer, the world's authority on cancer research. In particular, exposure to ultraviolet radiation can lead to melanoma of the skin, which is the deadliest form of skin cancer in the United States. Yet despite the significant public health burden that is associated with skin cancer in the United States, each year over a million Americans engage in indoor tanning where exposure to artificial ultraviolet radiation occurs. In this article, we argue for an immediate ban on the use of commercial indoor tanning by minors and, based on international precedents, the phasing out of all commercial tanning operations in the United States. We consider the use of indoor tanning devices in the United States, epidemiological data on indoor tanning devices and cancer, regulation of tanning devices, and scientific evidence for increased government intervention.

Alcohol's effect on other chronic liver diseases.

In addition to directly causing liver disease, alcohol consumption is a common comorbid condition with other chronic liver diseases and may exacerbate liver injury, particularly in nonalcoholic fatty liver disease, chronic viral hepatitis, hereditary hemochromatosis, and autoimmune liver diseases. This synergism can result in increased hepatic inflammation and accelerated rates of fibrosis, with more rapid and earlier development of cirrhosis, and also increase the risk for liver cancer and death from liver disease.

Hepatitis B: modern end points of treatment and the specter of viral resistance.

The goal of antiviral treatment of chronic hepatitis B is to prevent the complications of cirrhosis, hepatic decompensation, HCC, and death. Because these clinical outcomes may take a long period of time to develop, it is important to use intermediate or surrogate end points to evaluate the efficacy and response to antiviral treatment, and to determine whether treatment can be safely stopped, especially given concern for the development of antiviral resistance with NUC therapy. Although normalization of ALT and suppression of HBV DNA viral replication are associated with favorable outcomes, the durability of their response is low, and these end points are insufficient markers for stopping treatment. HBeAg seroconversion is currently used to discontinue NUC treatment in patients with HBeAg-positive chronic hepatitis B, whereas the stopping rule for HBeAg-negative disease relies on HBsAg loss. However, HBsAg loss occurs very infrequently and is not a practical end point for clinical use, although quantitative HBsAg levels may be useful in identifying patients who could achieve a sustained virologic response to treatment.

KRIT1 association with the integrin-binding protein ICAP-1: a new direction in the elucidation of cerebral cavernous malformations (CCM1) pathogenesis.

Mutations in KRIT1, a protein initially identified based on a yeast two-hybrid interaction with the RAS-family GTPase RAP1A, are responsible for the development of the inherited vascular disorder cerebral cavernous malformations (CCM1). As the function of the KRIT1 protein and its role in CCM pathogenesis remain unknown, we performed yeast two-hybrid screens to identify additional protein binding partners. A fragment containing the N-terminal 272 amino acid residues of KRIT1, a region lacking similarity to any known protein upon database searches, was used as bait. From parallel screens of human fetal brain and HeLa cDNA libraries, we obtained multiple independent isolates of human integrin cytoplasmic domain-associated protein-1 (ICAP-1) as interacting clones. The interaction of KRIT1 and ICAP-1 was confirmed by GST-KRIT1 trapping of endogenous ICAP-1 from 293T cells. The alpha isoform of ICAP-1 is a 200 amino acid serine/threonine-rich phosphoprotein which binds the cytoplasmic tail of beta1 integrins. We show that mutagenesis of the N-terminal KRIT1 NPXY amino acid sequence, a motif critical for ICAP-1 binding to beta1 integrin molecules, completely abrogates the KRIT1/ICAP-1 interaction. The interaction between ICAP-1 and KRIT1, and the presence of a FERM domain in the latter, suggest that KRIT1 might be involved in the bidirectional signaling between integrin molecules and the cytoskeleton. Furthermore, these data suggest that KRIT1 might affect cell adhesion processes via integrin signaling in CCM1 pathogenesis.