Predicting COVID-19 and respiratory illness: results of the 2022-2023 Armed Forces Health Surveillance Division forecasting challenge.

Since 2019, the Integrated Biosurveillance Branch of the Armed Forces Health Surveillance Division has conducted an annual forecasting challenge during influenza season to predict short-term respiratory disease activity among Military Health System beneficiaries. Weekly case and encounter observed data were used to generate 1- through 4-week advanced forecasts of disease activity. To create unified combinations of model inputs for evaluation across multiple spatial resolutions, 8 individual models were used to calculate 3 ensemble models. Forecast accuracy compared to the observed activity for each model was evaluated by calculating a weighted interval score. Weekly 1- through 4-week ahead forecasts for each ensemble model were generally higher than observed data, especially during periods of peak activity, with peaks in forecasted activity occurring later than observed peaks. The larger the forecasting horizon, the more pronounced the gap between forecasted peak and observed peak. The results showed that several models accurately predicted COVID-19 cases and respiratory encounters with enough lead time for public health response by senior leaders.

The association between frequency of opioid misuse and opioid use disorder among youth and adults in the United States.

BACKGROUND: Studies have shown the frequency of drug misuse is important in the development of a substance use disorder, but little is known about this relationship in the context of opioid misuse and opioid use disorder and withdrawal symptoms. METHODS: Our study included 2694 civilian respondents from the United States 12 years and older who had misused prescription opioids in the past year from the 2014 National Survey on Drug Use and Health. Logistic regression was used to model the association between frequency of prescription opioid misuse and opioid use disorder and withdrawal symptoms, adjusting for age, sex, race/ethnicity, and income level. RESULTS: Misusing prescription opioids more frequently was significantly associated with opioid use disorder in a dose-dependent manner (daily misuse: OR = 14.92, 95% confidence interval (CI) 9.29, 23.95; 1-2 days/week: OR = 4.46 95% CI: 2.52, 7.89}; 1-4 times/month: OR = 2.40, 95% CI: 1.37, 4.18) compared to use less than 1 time a month. OR = 2.89, 95% CI 1.90, 4.40, respectively) after controlling for sex, age, race/ethnicity, and income. A dose-dependent relationship was found between frequency of opioid misuse and withdrawal symptoms (daily misuse: OR = 2.89, 95% CI: 1.90, 4.40; 1-2 times/week: OR = 1.91, 95% CI: 1.05, 3.45; and 1-4 times/month: 1.74, 95% CI: 1.90, 4.40) after controlling for all covariates mentioned above. CONCLUSIONS: Our results provide evidence that higher frequency of opioid misuse is associated with both opioid use disorder and withdrawal symptoms. Frequency of use should be considered in the development of more effective opioid use disorder prevention strategies.

Microfilariae of Brugia malayi Inhibit the mTOR Pathway and Induce Autophagy in Human Dendritic Cells.

Immune modulation is a hallmark of patent filarial infection, including suppression of antigen-presenting cell function and downmodulation of filarial antigen-specific T cell responses. The mammalian target of rapamycin (mTOR) signaling pathway has been implicated in immune regulation, not only by suppressing T cell responses but also by regulating autophagy (through mTOR sensing amino acid availability). Global proteomic analysis (liquid chromatography-tandem mass spectrometry) of microfilaria (mf)-exposed monocyte-derived dendritic cells (DC) indicated that multiple components of the mTOR signaling pathway, including mTOR, eIF4A, and eIF4E, are downregulated by mf, suggesting that mf target this pathway for immune modulation in DC. Utilizing Western blot analysis, we demonstrate that similar to rapamycin (a known mTOR inhibitor), mf downregulate the phosphorylation of mTOR and its regulatory proteins, p70S6K1 and 4E-BP1, a process essential for DC protein synthesis. As active mTOR signaling regulates autophagy, we examined whether mf exposure alters autophagy-associated processes. mf-induced autophagy was reflected in marked upregulation of phosphorylated Beclin 1, known to play an important role in both autophagosome formation and autolysosome fusion, in induction of LC3II, a marker of autophagosome formation, and in induced degradation of p62, a ubiquitin-binding protein that aggregates protein in autophagosomes and is degraded upon autophagy that was reduced significantly by mf exposure and by rapamycin. Together, these results suggest that Brugia malayi mf employ mechanisms of metabolic modulation in DC to influence the regulation of the host immune response by downregulating mTOR signaling, resulting in increased autophagy. Whether this is a result of the parasite-secreted rapamycin homolog is currently under study.

Novel CARM1-Interacting Protein, DZIP3, Is a Transcriptional Coactivator of Estrogen Receptor-α.

Coactivator-associated arginine methyltransferase 1 (CARM1) is known to promote estrogen receptor (ER)α-mediated transcription in breast cancer cells. To further characterize the regulation of ERα-mediated transcription by CARM1, we screened CARM1-interacting proteins by yeast two-hybrid. Here, we have identified an E3 ubiquitin ligase, DAZ (deleted in azoospermia)-interacting protein 3 (DZIP3), as a novel CARM1-binding protein. DZIP3-dependent ubiquitination of histone H2A has been associated with repression of transcription. However, ERα reporter gene assays demonstrated that DZIP3 enhanced ERα-mediated transcription and cooperated synergistically with CARM1. Interaction with CARM1 was observed with the E3 ligase RING domain of DZIP3. The methyltransferase activity of CARM1 partially contributed to the synergy with DZIP3 for transcription activation, but the E3 ubiquitin ligase activity of DZIP3 was dispensable. DZIP3 also interacted with the C-terminal activation domain 2 of glucocorticoid receptor-interacting protein 1 (GRIP1) and enhanced the interaction between GRIP1 and CARM1. Depletion of DZIP3 by small interfering RNA in MCF7 cells reduced estradiol-induced gene expression of ERα target genes, GREB1 and pS2, and DZIP3 was recruited to the estrogen response elements of the same ERα target genes. These results indicate that DZIP3 is a novel coactivator of ERα target gene expression.