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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infections in vaccinated individuals and reinfections in previously infected individuals have become increasingly common. Such infections highlight a broader need to understand the contribution of vaccination, including booster doses, and natural immunity to the infectiousness of individuals with SARS-CoV-2 infections, especially in high-risk populations with intense transmission, such as in prisons. Here we show that both vaccine-derived and naturally acquired immunity independently reduce the infectiousness of persons with Omicron variant SARS-CoV-2 infections in a prison setting. Analyzing SARS-CoV-2 surveillance data from December 2021 to May 2022 across 35 California state prisons with a predominately male population, we estimate that unvaccinated Omicron cases had a 36% (95% confidence interval (CI): 31–42%) risk of transmitting infection to close contacts, as compared to a 28% (25–31%) risk among vaccinated cases. In adjusted analyses, we estimated that any vaccination, prior infection alone and both vaccination and prior infection reduced an index case’s risk of transmitting infection by 22% (6–36%), 23% (3–39%) and 40% (20–55%), respectively. Receipt of booster doses and more recent vaccination further reduced infectiousness among vaccinated cases. These findings suggest that, although vaccinated and/or previously infected individuals remain highly infectious upon SARS-CoV-2 infection in this prison setting, their infectiousness is reduced compared to individuals without any history of vaccination or infection. This study underscores benefit of vaccination to reduce, but not eliminate, transmission. Analysis of data from California prisons shows that both COVID-19 vaccination and prior SARS-CoV-2 infection reduces the risk of virus transmission to close contacts.

The explosive outbreaks of COVID-19 seen in congregate settings such as prisons and nursing homes, has highlighted a critical need for effective outbreak prevention and mitigation strategies for these settings. Here we consider how different types of control interventions impact the expected number of symptomatic infections due to outbreaks. Introduction of disease into the resident population from the community is modeled as a stochastic point process coupled to a branching process, while spread between residents is modeled via a deterministic compartmental model that accounts for depletion of susceptible individuals. Control is modeled as a proportional decrease in the number of susceptible residents, the reproduction number, and/or the proportion of symptomatic infections. This permits a range of assumptions about the density dependence of transmission and modes of protection by vaccination, depopulation and other types of control. We find that vaccination or depopulation can have a greater than linear effect on the expected number of cases. For example, assuming a reproduction number of 3.0 with density-dependent transmission, we find that preemptively reducing the size of the susceptible population by 20% reduced overall disease burden by 47%. In some circumstances, it may be possible to reduce the risk and burden of disease outbreaks by optimizing the way a group of residents are apportioned into distinct residential units. The optimal apportionment may be different depending on whether the goal is to reduce the probability of an outbreak occurring, or the expected number of cases from outbreak dynamics. In other circumstances there may be an opportunity to implement reactive disease control measures in which the number of susceptible individuals is rapidly reduced once an outbreak has been detected to occur. Reactive control is most effective when the reproduction number is not too high, and there is minimal delay in implementing control. We highlight the California state prison system as an example for how these findings provide a quantitative framework for understanding disease transmission in congregate settings. Our approach and accompanying interactive website ( https://phoebelu.shinyapps.io/DepopulationModels/ ) provides a quantitative framework to evaluate the potential impact of policy decisions governing infection control in outbreak settings.

Small molecules are useful tools for probing the biological function and therapeutic potential of individual proteins, but achieving selectivity is challenging when the target protein shares structural domains with other proteins. The Bromo and Extra-Terminal (BET) proteins have attracted interest because of their roles in transcriptional regulation, epigenetics, and cancer. The BET bromodomains (protein interaction modules that bind acetyl-lysine) have been targeted by potent small-molecule inhibitors, but these inhibitors lack selectivity for individual family members. We developed an ethyl derivative of an existing small-molecule inhibitor, I-BET/JQ1, and showed that it binds leucine/alanine mutant bromodomains with nanomolar affinity and achieves up to 540-fold selectivity relative to wild-type bromodomains. Cell culture studies showed that blockade of the first bromodomain alone is sufficient to displace a specific BETprotein, Brd4, from chromatin. Expansion of this approach could help identify the individual roles of single BETproteins in human physiology and disease.

Racial and ethnic minoritized groups and socioeconomically disadvantaged communities experience longstanding health-related disparities in the United States and were disproportionately affected throughout the COVID-19 pandemic. How departments of public health can explicitly address these disparities and their underlying determinants remains less understood. To inform future public health responses, this paper details how California strategically placed health equity at the core of its COVID-19 reopening and response policy, known as the Blueprint for a Safer Economy . In effect from August 2020 to June 2021, “the Blueprint” employed the use of the California Healthy Places Index (HPI), a place-based summary measure of 25 determinants of health constructed at the census tract level, to guide activities. Using California’s approach, we categorized the state population by HPI quartiles at the state and within-county levels (HPIQ1 representing the least advantaged, HPIQ4, the most advantaged) from HPI data available to demonstrate how the state monitored crude COVID-19 test, case, mortality, and vaccine rates and unadjusted rate ratios (RR) using equity metrics developed for the Blueprint. Notable patterns emerged. Testing disparities disappeared during the summer and winter surges but resurfaced between surges. Monthly case RR peaked in May 2020 for HPIQ1 compared to HPIQ4 (RR 6.61, 95%CI: 6.41–6.81), followed by mortality RR peaking in June 2020 (RR 5.06, 95% CI: 4.34–5.91). As the pandemic wore on, disparities in unadjusted case and mortality RRs between lower HPI quartiles relative to HPIQ4 reduced but remained. Utilizing a place-based index, such as HPI, enabled a data-driven approach that used a determinants of health lens to identify priority communities, allocate resources, and monitor outcomes based on need during a large-scale public health emergency.

Circulating tumor cells (CTCs) are shed into the bloodstream by invasive cancers, but the difficulty inherent in identifying these rare cells by microscopy has precluded their routine use in monitoring or screening for cancer. We recently described a high-throughput microfluidic CTC-iChip, which efficiently depletes hematopoietic cells from blood specimens and enriches for CTCs with well-preserved RNA. Application of RNA-based digital PCR to detect CTC-derived signatures may thus enable highly accurate tissue lineage-based cancer detection in blood specimens. As proof of principle, we examined hepatocellular carcinoma (HCC), a cancer that is derived from liver cells bearing a unique gene expression profile. After identifying a digital signature of 10 liver-specific transcripts, we used a cross-validated logistic regression model to identify the presence of HCC-derived CTCs in nine of 16 (56%) untreated patients with HCC versus one of 31 (3%) patients with nonmalignant liver disease at risk for developing HCC (P < 0.0001). Positive CTC scores declined in treated patients: Nine of 32 (28%) patients receiving therapy and only one of 15 (7%) patients who had undergone curative-intent ablation, surgery, or liver transplantation were positive. RNA-based digital CTC scoring was not correlated with the standard HCC serum protein marker alpha fetoprotein (P = 0.57). Modeling the sequential use of these two orthogonal markers for liver cancer screening in patients with high-risk cirrhosis generates positive and negative predictive values of 80% and 86%, respectively. Thus, digital RNA quantitation constitutes a sensitive and specific CTC readout, enabling high-throughput clinical applications, such as noninvasive screening for HCC in populations where viral hepatitis and cirrhosis are prevalent.

Early investigation revealed a reduced risk of SARS-CoV-2 infection among social contacts of COVID-19 vaccinated individuals, referred to as indirect protection. However, indirect protection from SARS-CoV-2 infection-acquired immunity and its comparative strength and durability to vaccine-derived indirect protection in the current epidemiologic context of high levels of vaccination, prior infection, and novel variants are not well characterized. Here, we show that both vaccine-derived and infection-acquired immunity independently yield indirect protection to close social contacts with key differences in their strength and waning. Analyzing anonymized SARS-CoV-2 surveillance data from 9,625 residents in California state prisons from December 2021 to December 2022, we find that vaccine-derived indirect protection against Omicron SARS-CoV-2 infection is strongest within three months of COVID-19 vaccination [30% (95% confidence interval: 20–38%)] with subsequent modest protection. Infection-acquired immunity provides 38% (24–50%) indirect protection for 6 months after SARS-CoV-2 infection, with moderate indirect protection persisting for over one year. Variant-targeted vaccines (bivalent formulation including Omicron subvariants BA.4/BA.5) confer strong indirect protection for at least three months [40% (3–63%)]. These results demonstrate that both vaccine-derived and infection-acquired immunity can reduce SARS-CoV-2 transmission which is important for understanding long-term transmission dynamics and can guide public health intervention, especially in high-risk environments such as prisons. Vaccines and infection-acquired immunity reduce infection risk to close contacts through ‘indirect protection’. Here, the authors characterise the strength and durability of vaccine- and infection-acquired indirect protection against SARS-CoV-2 using surveillance data from residents of state prisons in California.

The inner ear is essential for maintaining balance and hearing predator and prey in the environment. Each inner ear contains three CaCO3 otolith polycrystals, which are calcified within an alkaline, K+-rich endolymph secreted by the surrounding epithelium. However, the underlying cellular mechanisms are poorly understood, especially in marine fish. Here, we investigated the presence and cellular localization of several ion-transporting proteins within the saccular epithelium of the Pacific Chub Mackerel (Scomber japonicus). Western blotting revealed the presence of Na+/K+-ATPase (NKA), carbonic anhydrase (CA), Na+-K+-2Cl−-co-transporter (NKCC), vacuolar-type H+-ATPase (VHA), plasma membrane Ca2+ ATPase (PMCA), and soluble adenylyl cyclase (sAC). Immunohistochemistry analysis identified two distinct ionocytes types in the saccular epithelium: Type-I ionocytes were mitochondrion-rich and abundantly expressed NKA and NKCC in their basolateral membrane, indicating a role in secreting K+ into the endolymph. On the other hand, Type-II ionocytes were enriched in cytoplasmic CA and VHA, suggesting they help transport HCO3− into the endolymph and remove H+. In addition, both types of ionocytes expressed cytoplasmic PMCA, which is likely involved in Ca2+ transport and homeostasis, as well as sAC, an evolutionary conserved acid–base sensing enzyme that regulates epithelial ion transport. Furthermore, CA, VHA, and sAC were also expressed within the capillaries that supply blood to the meshwork area, suggesting additional mechanisms that contribute to otolith calcification. This information improves our knowledge about the cellular mechanisms responsible for endolymph ion regulation and otolith formation, and can help understand responses to environmental stressors such as ocean acidification.

Background Nicotine use and nicotine use disorder (NUD) are the leading causes of preventable death in the United States. Persons with mental disorders  (e.g., bipolar disorder) are differentially susceptible to nicotine use. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are indicated for type 2 diabetes mellitus (T2DM) and obesity and show preliminary evidence of efficacy in addiction-related behaviours. Herein, we synthesize extant preclinical and clinical evidence evaluating the effect of GLP-1RAs on neurobiological systems and behaviours salient to nicotine consumption and cessation. Methods Online databases (MedLine, Embase, AMED, PsychINFO, JBI EBP Database, PubMed, Web of Science, Google Scholar) were searched from inception to May 21, 2024. Relevant studies were also extracted from the reference lists of the obtained articles. All articles were screened against inclusion and exclusion criteria. Results Administration of GLP-1RAs reduced nicotine self-administration and nicotine-seeking behaviour in animal models that, in some cases, is sustained beyond exposure to the agent. GLP-1RAs also mitigated post-nicotine cessation weight gain, craving, withdrawal, and hyperphagia. The preceding effects are attributable to modulation of reward-related brain regions (e.g., mesolimbic dopamine system), resulting in nicotine aversion. GLP-1RAs were also efficacious as adjunctive therapies [e.g., in combination with nicotine replacement therapies (NRTs)]. Conclusion The multi-effect characteristics in NUD paradigms provide a compelling rationale for large, adequately powered, long-term, randomized controlled trials of GLP-1RAs in the treatment and prevention of NUD. The replicated effect on mitigating post-nicotine cessation weight gain is a differentiating feature of GLP-1RAs from extant proven therapies for NUD.

Background People incarcerated in US prisons have been disproportionately harmed by the COVID-19 pandemic. That prisons are such efficient superspreading environments can be attributed to several known factors: small, communal facilities where people are confined for prolonged periods of time; poor ventilation; a lack of non-punitive areas for quarantine/medical isolation; and staggeringly high numbers of people experiencing incarceration, among others. While health organizations have issued guidance on preventing and mitigating COVID-19 infection in carceral settings, little is known about if, when, and how recommendations have been implemented. We examined factors contributing to containment of one of the first California prison COVID-19 outbreaks and remaining vulnerabilities using an adapted multi-level determinants framework to systematically assess infectious disease risk in carceral settings. Methods Case study employing administrative data; observation; and informal discussions with: people incarcerated at the prison, staff, and county public health officials. Results Outbreak mitigation efforts were characterized by pre-planning (e.g., designation of ventilated, single-occupancy quarantine) and a quickly mobilized inter-institutional response that facilitated systematic, voluntary rapid testing. However, several systemic- and institutional-level vulnerabilities were unaddressed hindering efforts and posing significant risk for future outbreaks, including insufficient decarceration, continued inter-facility transfers, incomplete staff cohorting, and incompatibility between built environment features (e.g., dense living conditions) and public health recommendations. Conclusions Our adapted framework facilitates systematically assessing prison-based infectious disease outbreaks and multi-level interventions. We find implementing some recommended public health strategies may have contributed to outbreak containment. However, even with a rapidly mobilized, inter-institutional response, failure to decarcerate created an overreliance on chance conditions. This left the facility vulnerable to future catastrophic outbreaks and may render standard public health strategies - including the introduction of effective vaccines - insufficient to prevent or contain those outbreaks.

Dextromethorphan/bupropion (DXM/BUP) received Food and Drug Administration (FDA) approval for the treatment of adults with major depressive disorder (MDD) in August 2022. This combination is not known to have abuse liability and is not currently scheduled by the Drug Enforcement Administration (DEA). Notwithstanding, dextromethorphan is a drug of abuse. Herein, we sought to determine whether DXM/BUP has alcohol and/or substance misuse liability. We evaluated spontaneous reports of terms such as \"alcohol problem, alcoholism, alcohol abuse, substance dependence, substance use disorder (SUD), substance abuse, drug dependence, drug use disorder and drug abuse\" in the FDA Adverse Event Reporting System (FAERS). The FAERS is a spontaneous reporting database of adverse events submitted to the FDA. We performed a comparative assessment of the alcohol and/or substance misuse liability of DXM/BUP since its market authorization in August 2022, using acetaminophen as the control. Dextromethorphan served as the upper-bound reference point. Our findings showed that, since August 2022, dextromethorphan had a significant reporting odds ratio (ROR) for \"drug abuse.\" In contrast, DXM/BUP did not have a significant ROR for any of the categories of alcohol and/or substance misuse evaluated. Limitations of our findings derive largely from the limitations of the FAERS and its data capture method. The absence of alcohol or substance misuse reported to the FAERS with DXM/BUP accords with the lack of evidence of abuse liability prior to FDA approval and its non-scheduling by the DEA.