Mpox Outbreak - Los Angeles County, California, May 4-August 17, 2023.

Since May 2022, approximately 2,500 mpox cases have been reported in Los Angeles County (LAC), California. Beginning in May 2023, the LAC Department of Public Health observed a consistent increase in mpox cases after a prolonged period of low incidence. A total of 56 cases were identified during May 4-August 17, 2023. A minority of mpox patients were fully vaccinated (29%). One patient was hospitalized; no deaths were reported. Two cases of reinfection occurred, both of which were associated with mild illness. The increasing number of cases during this period was significant, as few other health departments in the United States reported an increase in mpox cases during the same period. The outbreak spread similarly to the 2022 U.S. mpox outbreak, mainly through sexual contact among gay, bisexual, and other men who have sex with men. Vaccination against mpox became available in June 2022 and has been shown to be effective at preventing mpox disease. This outbreak was substantially smaller than the 2022 mpox outbreak in LAC (2,280 cases); possible explanations for the lower case count include increased immunity provided from vaccination against mpox and population immunity from previous infections. Nonetheless, mpox continues to spread within LAC, and preventive measures, such as receipt of JYNNEOS vaccination, are recommended for persons at risk of Monkeypox virus exposure.

BRP39 Regulates Neutrophil Recruitment in NLRP3 Inflammasome-Induced Liver Inflammation.

BACKGROUND & AIMS: Breast regression protein 39 (BRP39) (Chi3L1) and its human homolog YKL-40, is an established biomarker of liver fibrosis in nonalcoholic steatohepatitis (NASH) patients, but its role in NASH pathogenesis remains unclear. We recently identified Chi3L1 as one of the top up-regulated genes in mice with inducible gain-of-function NOD-like receptor protein 3 (NLRP3) activation that mimics several liver features of NASH. This study aimed to investigate the effects of BRP39 deficiency on NLRP3-induced liver inflammation using tamoxifen-inducible Nlrp3 knockin mice sufficient (Nlrp3A350V CRT) and deficient for BRP39 (Nlrp3A350V/BRP-/- CRT). METHODS: Using Nlrp3A350V CRT mice and Nlrp3A350V BRP-/- CRT, we investigated the consequences of BRP39 deficiency influencing NLRP3-induced liver inflammation. RESULTS: Our results showed that BRP39 deficiency in NLRP3-induced inflammation improved body weight and liver weight. Moreover, liver inflammation, fibrosis, and hepatic stellate cell activation were reduced significantly, corresponding to significantly decreased Ly6C+ infiltrating macrophages, CD68+ osteopontin-positive hepatic lipid-associated macrophages, and activated Lymphocyte antigen 6 complex locus G6D positive (Ly6G+) and citrullinated histone H3 postivie (H3Cit+) neutrophil accumulation in the liver. Further investigation showed that circulatory neutrophils from NLRP3-induced BRP39-deficient mice have impaired chemotaxis and migration ability, and this was confirmed by RNA bulk sequencing showing reduced immune activation, migration, and signaling responses in neutrophils. CONCLUSIONS: These data showcase the importance of BRP39 in regulating the NLRP3 inflammasome during liver inflammation and fibrotic NASH by altering cellular activation, recruitment, and infiltration during disease progression, and revealing BRP39 to be a potential therapeutic target for future treatment of inflammatory NASH and its associated diseases.

Countering Mpox Vaccination Disparities in Los Angeles County, California, May-December 2022.

Providing equitable access to vaccines for individuals at risk for mpox was critical for containing the 2022 mpox outbreak in Los Angeles County, California. Eligible non-Hispanic Black/African American and Latinx individuals had lower vaccine uptake than did non-Hispanic White individuals, despite having higher mpox case rates. Strategies to address disparities in vaccine uptake included using familiar messaging technology to reach individuals at risk for mpox, using partnerships with community-based organizations to raise mpox awareness, and bringing vaccines to locations convenient to at-risk individuals to improve access. (Am J Public Health. 2023;113(12):1258-1262. https://doi.org/10.2105/AJPH.2023.307409).

Myeloid-specific deletion of chitinase-3-like 1 protein ameliorates murine diet-induced steatohepatitis progression.

Chitinase-3-like 1 protein (CHI3L1) is a secreted glycoprotein, strongly correlated with fibrosis severity in chronic liver diseases including non-alcoholic steatohepatitis (NASH). However, the mechanisms by which CHI3L1 contributes to fibrogenesis remain undefined. Here, we showed that infiltrating monocyte-derived liver macrophages represent the main source of CHI3L1 in murine NASH. We developed a floxed CHI3L1 knock-out (KO) mouse to further study the cell-specific role of CHI3L1 ablation. Wildtype (WT) and myeloid cell-specific CHI3L1 KO mice (CreLyz) were challenged with a highly inflammatory and fibrotic dietary model of NASH by administering choline-deficient high-fat diet for 10 weeks. Macrophage accumulation and inflammatory cell recruitment were significantly ameliorated in the CreLyz group compared to WT (F4/80 IHC p < 0.0001, CD11b IHC p < 0.0001). Additionally, hepatic stellate cell (HSC) activation and fibrosis were strongly decreased in this group (α-SMA IHC p < 0.0001, picrosirius red staining p < 0.0001). In vitro studies were performed stimulating bone marrow derived macrophages, THP-1 (human monocytes) and LX2 (human HSCs) cells with recombinant CHI3L1 to dissect its relationship with fibrosis development. Results showed an important role of CHI3L1 regulating fibrosis-promoting factors by macrophages (TGFB1 p < 0.05, CTGF p < 0.01) while directly activating HSCs (ACTA2 p < 0.01, COL1A1 p < 0.01), involving IL13Rα2 as the potential mediator. Our findings uncovered a novel role of CHI3L1 derived from liver macrophages in NASH progression and identifies this protein as a potential anti-fibrotic therapeutic target. KEY MESSAGES: We showed that CHI3L1 expression is increased in murine CDAA-HFAT diet NASH model, and that infiltrating macrophages are a key source of CHI3L1 production. Myeloid cell-specific CreLyz CHI3L1 knock-out in mice fed with CDAA-HFAT diet improved the NASH phenotype, with significantly reduced accumulation of pro-inflammatory macrophages and neutrophils compared with WT group. DEG and qPCR analysis of genes in CreLyz CHI3L1 knock-out mouse liver showed the mechanistic role of CHI3L1 in cellular chemotaxis. HSC is directly activated by CHI3L1 via receptor IL13Rα2, leading to upregulation of collagen deposition and pro-fibrotic gene, TIMP-1 and TIMP-2 release in whole liver. Direct stimulation of macrophages with CHI3L1 leads to upregulated expression of HSC-activation factors, suggesting its role in modulating macrophage-HSC crosstalk.

HIV Incidence, Recent HIV Infection, and Associated Factors, Kenya, 2007-2018.

Nationally representative surveys provide an opportunity to assess trends in recent human immunodeficiency virus (HIV) infection based on assays for recent HIV infection. We assessed HIV incidence in Kenya in 2018 and trends in recent HIV infection among adolescents and adults in Kenya using nationally representative household surveys conducted in 2007, 2012, and 2018. To assess trends, we defined a recent HIV infection testing algorithm (RITA) that classified as recently infected (<12 months) those HIV-positive participants that were recent on the HIV-1 limiting antigen (LAg)-avidity assay without evidence of antiretroviral use. We assessed factors associated with recent and long-term (≥12 months) HIV infection versus no infection using a multinomial logit model while accounting for complex survey design. Of 1,523 HIV-positive participants in 2018, 11 were classified as recent. Annual HIV incidence was 0.14% in 2018 [95% confidence interval (CI) 0.057-0.23], representing 35,900 (95% CI 16,300-55,600) new infections per year in Kenya among persons aged 15-64 years. The percentage of HIV infections that were determined to be recent was similar in 2007 and 2012 but fell significantly from 2012 to 2018 [adjusted odds ratio (aOR) = 0.31, p < .001]. Compared to no HIV infection, being aged 25-34 versus 35-64 years (aOR = 4.2, 95% CI 1.4-13), having more lifetime sex partners (aOR = 5.2, 95% CI 1.6-17 for 2-3 partners and aOR = 8.6, 95% CI 2.8-26 for ≥4 partners vs. 0-1 partners), and never having tested for HIV (aOR = 4.1, 95% CI 1.5-11) were independently associated with recent HIV infection. Although HIV remains a public health priority in Kenya, HIV incidence estimates and trends in recent HIV infection support a significant decrease in new HIV infections from 2012 to 2018, a period of rapid expansion in HIV diagnosis, prevention, and treatment.

Spatiotemporal image quality of virtual reality head mounted displays.

Virtual reality (VR) head mounted displays (HMDs) require both high spatial resolution and fast temporal response. However, methods to quantify the VR image quality in the spatiotemporal domain when motion exists are not yet standardized. In this study, we characterize the spatiotemporal capabilities of three VR devices: the HTC VIVE, VIVE Pro, and VIVE Pro 2 during smooth pursuit. A spatiotemporal model for VR HMDs is presented using measured spatial and temporal characteristics. Among the three evaluated headsets, the VIVE Pro 2 improves the display temporal performance using a fast 120 Hz refresh rate and pulsed emission with a small duty cycle of 5%. In combination with a high pixel resolution beyond 2 k [Formula: see text] 2 k per eye, the VIVE Pro 2 achieves an improved spatiotemporal performance compared to the VIVE and VIVE Pro in the high spatial frequency range above 8 cycles per degree during smooth pursuit. The result demonstrates that reducing the display emission duty cycle to less than 20% is beneficial to mitigate motion blur in VR HMDs. Frame rate reduction (e.g., to below 60 Hz) of the input signal compared to the display refresh rate of 120 Hz yields replicated shadow images that can affect the image quality under motion. This work supports the regulatory science research efforts in development of testing methods to characterize the spatiotemporal performance of VR devices for medical use.

Analytical comparability demonstrated for an IgG4 molecule, inclacumab, following transfer of manufacturing responsibility from Roche to Global Blood Therapeutics.

BACKGROUND: Inclacumab is a recombinant, fully human, immunoglobulin IgG4 monoclonal antibody that selectively binds to P-selectin. Initially discovered and developed by Roche through phase 2 clinical studies in peripheral arterial disease and coronary artery disease, inclacumab has been in-licensed by Global Blood Therapeutics (GBT) as a potential treatment to reduce the frequency of vaso-occlusive crises in individuals with sickle cell disease. RESEARCH DESIGN AND METHODS: GBT sought to demonstrate the analytical comparability between material produced by Roche and material produced by GBT to ensure that no meaningful differences in identity, safety, purity, potency, or bioavailability exist between the GBT and Roche lots. RESULTS: Inclacumab samples produced by GBT were found to be comparable to the Roche v0.2 inclacumab samples based on (1) comparable primary and higher-order structures; (2) comparable purity profiles; (3) comparable potency, in vitro functional activities, and in vivo plasma exposures and pharmacokinetic profiles; and (4) comparable degradation patterns and kinetics under forced degradation conditions. CONCLUSIONS: Based on the design of this comparability study and the results obtained, the US Food and Drug Administration approved the changes to the manufacturing process and gave clearance for GBT to proceed with phase 3 clinical trials.

Cell-specific Deletion of NLRP3 Inflammasome Identifies Myeloid Cells as Key Drivers of Liver Inflammation and Fibrosis in Murine Steatohepatitis.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide. The NLRP3 inflammasome, a platform for caspase-1 activation and release of interleukin 1ß, is increasingly recognized in the induction of inflammation and liver fibrosis during NAFLD. However, the cell-specific contribution of NLRP3 inflammasome activation in NAFLD remains unknown. METHODS: To investigate the role of NLRP3 inflammasome activation in hepatocytes, hepatic stellate cells (HSCs) and myeloid cells, a conditional Nlrp3 knock-out mouse was generated and bred to cell-specific Cre mice. Both acute and chronic liver injury models were used: lipopolysaccharide/adenosine-triphosphate to induce in vivo NLRP3 activation, choline-deficient, L-amino acid-defined high-fat diet, and Western-type diet to induce fibrotic nonalcoholic steatohepatitis (NASH). In vitro co-culture studies were performed to dissect the crosstalk between myeloid cells and HSCs. RESULTS: Myeloid-specific deletion of Nlrp3 blunted the systemic and hepatic increase in interleukin 1ß induced by lipopolysaccharide/adenosine-triphosphate injection. In the choline-deficient, L-amino acid-defined high-fat diet model of fibrotic NASH, myeloid-specific Nlrp3 knock-out but not hepatocyte- or HSC-specific knock-out mice showed significant reduction in inflammation independent of steatosis development. Moreover, myeloid-specific Nlrp3 knock-out mice showed ameliorated liver fibrosis and decreased HSC activation. These results were validated in the Western-type diet model. In vitro co-cultured studies with human cell lines demonstrated that HSC can be activated by inflammasome stimulation in monocytes, and this effect was significantly reduced if NLRP3 was downregulated in monocytes. CONCLUSIONS: The study provides new insights in the cell-specific role of NLRP3 in liver inflammation and fibrosis. NLRP3 inflammasome activation in myeloid cells was identified as crucial for the progression of NAFLD to fibrotic NASH. These results may have implications for the development of cell-specific strategies for modulation of NLRP3 activation for treatment of fibrotic NASH.

The difference between cystatin C- and creatinine-based assessment of kidney function in acute heart failure.

AIMS: Acute heart failure (HF) is associated with muscle mass loss, potentially leading to overestimation of kidney function using serum creatinine-based estimated glomerular filtration rate (eGFRsCr ). Cystatin C-based eGFR (eGFRCysC ) is less muscle mass dependent. Changes in the difference between eGFRCysC and eGFRsCr may reflect muscle mass loss. We investigated the difference between eGFRCysC and eGFRsCr and its association with clinical outcomes in acute HF patients. METHODS AND RESULTS: A post hoc analysis was performed in 841 patients enrolled in three trials: Diuretic Optimization Strategy Evaluation (DOSE), Renal Optimization Strategies Evaluation (ROSE), and Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF). Intra-individual differences between eGFRs (eGFRdiff ) were calculated as eGFRCysC -eGFRsCr at serial time points during HF admission. We investigated associations of (i) change in eGFRdiff between baseline and day 3 or 4 with readmission-free survival up to day 60; (ii) index hospitalization length of stay (LOS) and readmission with eGFRdiff at day 60. eGFRCysC reclassified 40% of samples to more advanced kidney dysfunction. Median eGFRdiff was -4 [-11 to 1.5] mL/min/1.73 m2 at baseline, became more negative during admission and remained significantly different at day 60. The change in eGFRdiff between baseline and day 3 or 4 was associated with readmission-free survival (adjusted hazard ratio per standard deviation decrease in eGFRdiff : 1.14, P = 0.035). Longer index hospitalization LOS and readmission were associated with more negative eGFRdiff at day 60 (both P ≤ 0.026 in adjusted models). CONCLUSIONS: In acute HF, a marked difference between eGFRCysC and eGFRsCr is present at baseline, becomes more pronounced during hospitalization, and is sustained at 60 day follow-up. The change in eGFRdiff during HF admission and eGFRdiff at day 60 are associated with clinical outcomes.

Evaluation Challenges for the Application of Extended Reality Devices in Medicine.

Augmented and virtual reality devices are being actively investigated and implemented for a wide range of medical uses. However, significant gaps in the evaluation of these medical devices and applications hinder their regulatory evaluation. Addressing these gaps is critical to demonstrating the devices' safety and effectiveness. We outline the key technical and clinical evaluation challenges discussed during the US Food and Drug Administration's public workshop, "Medical Extended Reality: Toward Best Evaluation Practices for Virtual and Augmented Reality in Medicine" and future directions for evaluation method development. Evaluation challenges were categorized into several key technical and clinical areas. Finally, we highlight current efforts in the standards communities and illustrate connections between the evaluation challenges and the intended uses of the medical extended reality (MXR) devices. Participants concluded that additional research is needed to assess the safety and effectiveness of MXR devices across the use cases.

Geospatial Transmission Hotspots of Recent HIV Infection - Malawi, October 2019-March 2020.

Persons infected with HIV are more likely to transmit the virus during the early stages (acute and recent) of infection, when viral load is elevated and opportunities to implement risk reduction are limited because persons are typically unaware of their status (1,2). Identifying recent HIV infections (acquired within the preceding 12 months)* is critical to understanding the factors and geographic areas associated with transmission to strengthen program intervention, including treatment and prevention (2). During June 2019, a novel recent infection surveillance initiative was integrated into routine HIV testing services in Malawi, a landlocked country in southeastern Africa with one of the world's highest prevalences of HIV infection.† The objectives of this initiative were to collect data on new HIV diagnoses, characterize the epidemic, and guide public health response (2). New HIV diagnoses were classified as recent infections based on a testing algorithm that included results from the rapid test for recent infection (RTRI)§ and HIV viral load testing (3,4). Among 9,168 persons aged ≥15 years with a new HIV diagnosis who received testing across 103 facilities during October 2019-March 2020, a total of 304 (3.3%) were classified as having a recent infection. Higher proportions of recent infections were detected among females, persons aged <30 years, and clients at maternal and child health and youth clinics. Using a software application that analyzes clustering in spatially referenced data, transmission hotspots were identified with rates of recent infection that were significantly higher than expected. These near real-time HIV surveillance data highlighted locations across Malawi, allowing HIV program stakeholders to assess program gaps and improve access to HIV testing, prevention, and treatment services. Hotspot investigation information could be used to tailor HIV testing, prevention, and treatment to ultimately interrupt transmission.

Gut-Selective Design of Orally Administered Izencitinib (TD-1473) Limits Systemic Exposure and Effects of Janus Kinase Inhibition in Nonclinical Species.

Izencitinib (TD-1473), an oral, gut-selective pan-Janus kinase (JAK) inhibitor under investigation for treatment of inflammatory bowel diseases, was designed for optimal efficacy in the gastrointestinal tract while minimizing systemic exposures and JAK-related safety findings. The nonclinical safety of izencitinib was evaluated in rat and dog repeat-dose and rat and rabbit reproductive and developmental toxicity studies. Systemic exposures were compared with JAK inhibitory potency to determine effects at or above pharmacologic plasma concentrations (≥1× plasma average plasma concentration [Cave]:JAK 50% inhibitory concentration [IC50] ratio). In rats and dogs, 1000 and 30 mg/kg/day izencitinib, respectively, produced minimal systemic findings (ie, red/white cell changes) and low systemic concentrations (approximately 1× plasma Cave:JAK IC50 ratio) with an 8× nonclinical:clinical systemic area under the curve (AUC) margin compared with exposures at the highest clinically tested dose (300 mg, quaque die, once daily, phase 1 study in healthy volunteers). In dogs, it was possible to attain sufficient systemic exposures to result in immunosuppression characteristic of systemic JAK inhibition, but at high AUC margins (43×) compared with systemic exposures observed at the highest tested dose in humans. No adverse findings were observed in the gastrointestinal tract or systemic tissues. Izencitinib did not affect male or female fertility. Izencitinib did not affect embryonic development in rats and rabbits as commonly reported with systemic JAK inhibition, consistent with low maternal systemic concentrations (2-6× plasma Cave:JAK IC50 ratio, 10-33× nonclinical:clinical AUC margin) and negligible fetal exposures. In conclusion, the izencitinib gut-selective approach resulted in minimal systemic findings in nonclinical species at pharmacologic, clinically relevant systemic exposures, highlighting the impact of organ-selectivity in reducing systemic safety findings.

Performance of a novel rapid test for recent HIV infection among newly-diagnosed pregnant adolescent girls and young women in four high-HIV-prevalence districts-Malawi, 2017-2018.

Tests for recent HIV infection (TRI) distinguish recent from long-term HIV infections using markers of antibody maturation. The limiting antigen avidity enzyme immunoassay (LAg EIA) is widely used with HIV viral load (VL) in a recent infection testing algorithm (RITA) to improve classification of recent infection status, estimate population-level HIV incidence, and monitor trends in HIV transmission. A novel rapid test for recent HIV infection (RTRI), Asanté™, can determine HIV serostatus and HIV recency within minutes on a lateral flow device through visual assessment of test strip or reader device. We conducted a field-based laboratory evaluation of the RTRI among pregnant adolescent girls and young women (AGYW) attending antenatal clinics (ANC) in Malawi.We enrolled pregnant AGYW aged <25 years testing HIV-positive for the first time at their first ANC visit from 121 ANCs in four high-HIV burden districts. Consenting participants provided blood for recency testing using LAg EIA and RTRI, which were tested in central laboratories. Specimens with LAg EIA normalized optical density values ≤2.0 were classified as probable recent infections. RTRI results were based on: (1) visual assessment: presence of a long-term line (LT) indicating non-recent infection and absence of the line indicating recent infection; or (2) a reader; specimens with LT line intensity units <3.0 were classified as probable recent infections. VL was measured for specimens classified as a probable recent infections by either assay; those with HIV-1 RNA ≥1,000 copies/mL were classified as confirmed recent infections. We evaluated the performance of the RTRI by calculating correlation between RTRI and LAg EIA results, and percent agreement and kappa between RTRI and LAg EIA RITA results.Between November 2017 to June 2018, 380 specimens were available for RTRI evaluation; 376 (98.9%) were confirmed HIV-positive on RTRI. Spearman's rho between RTRI and LAg EIA was 0.72 indicating strong correlation. Percent agreement and kappa between RTRI- and LAg EIA-based RITAs were >90% and >0.65 respectively indicating substantial agreement between the RITAs.This was the first field evaluation of an RTRI in sub-Saharan Africa, which demonstrated good performance of the assay and feasibility of integrating RTRI into routine HIV testing services for real-time surveillance of recent HIV infection.

Chronic intermittent intravenous immunoglobulin in heart transplant recipients with elevated donor-specific antibody levels.

Donor-specific antibodies (DSA) are associated with antibody-mediated rejection (AMR) and poor patient survival. In heart transplant, the efficacy of intermittent intravenous immunoglobulin (IVIg) in reducing de novo DSA levels and treating AMR has not been characterized. We retrospectively studied a cohort of 19 patients receiving intermittent IVIg for elevated DSA and examined changes in DSA levels and graft function. Intermittent IVIg infusions were generally safe and well tolerated. Overall, 23 of 62 total DSA (37%) were undetectable after treatment, 21 DSA (34%) had MFI decrease by more than 25%, and 18 (29%) had MFI decrease by less than 25% or increase. The average change in MFI was -51% ± 71% (P < .001). Despite reductions in DSA, among the six patients (32%) with biopsy-confirmed AMR, left ventricular ejection fraction (LVEF) decreased in five (83%) and cardiac index (CI) decreased in three (50%). Conversely, LVEF increased in 91% and CI increased in 70% of biopsy-negative patients. All six AMR patients were readmitted during treatment, four for confirmed or suspected rejection. IVIg infusions may stabilize the allograft in patients with elevated DSA and negative biopsies, but once AMR has developed does not appear to improve allograft function despite decreasing DSA levels.

Evaluation of a Test to Stay Strategy in Transitional Kindergarten Through Grade 12 Schools - Los Angeles County, California, August 16-October 31, 2021.

On July 12, 2021, the California Department of Public Health updated COVID-19 school guidance, allowing a Test to Stay (TTS) strategy to increase access to in-person learning* (1). The TTS strategy enabled unvaccinated students, exposed in school to a person infected with SARS-CoV-2 (the virus that causes COVID-19), to remain in school while under quarantine, if both the infected person and the exposed person wore masks correctly and consistently throughout the exposure. To stay in school during the quarantine period, the exposed student must remain asymptomatic, wear a mask at school, and undergo twice weekly testing for SARS-CoV-2. To date, few studies have evaluated the impact of TTS on transmission (2-4). This study evaluated a TTS strategy implemented by Los Angeles County Department of Public Health (LAC DPH). During September 20-October 31, 2021, among 78 school districts, one half permitted TTS; in total, 432 (21%) of 2,067 schools adopted TTS. TTS schools did not experience increases in COVID-19 incidence among students after TTS implementation, and in 20 identified outbreaks in TTS schools,† no tertiary transmission was identified. The ratio of student COVID-19 incidence in TTS districts to that in non-TTS districts was similar before and after TTS adoption (rate ratio = 0.5). Non-TTS schools lost an estimated 92,455 in-person school days during September 20-October 31 while students were in quarantine, compared with no lost days among quarantined students in TTS schools. Non-TTS schools cited resource-related reasons for not adopting TTS; 75% of these schools were in LAC's most disadvantaged neighborhoods. Preliminary data from LAC suggest that a school-based TTS strategy does not increase school transmission of SARS-CoV-2, and might greatly reduce loss of in-person school days; however, TTS might have barriers to implementation and require resources that are not available for some schools. Continued efforts to simplify school quarantine strategies might help to ensure that all students have access to safe in-person education. Although vaccination remains the leading public health recommendation to protect against COVID-19 for persons aged ≥5 years, schools might consider TTS as an option for allowing students with a school exposure who are not fully vaccinated to remain in the classroom as an alternative to home quarantine.

Dual role of neutrophils in modulating liver injury and fibrosis during development and resolution of diet-induced murine steatohepatitis.

Inflammatory changes in the liver represent a key feature of non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease (NAFLD). Innate immune activation including hepatic neutrophilic infiltration acts as an important inflammatory trigger as well as a potential mediator of inflammation resolution. In this study, we dissected the effects of neutrophil depletion via anti-lymphocyte antigen 6 complex locus G6D (Ly6G) antibodies administration during ongoing high fat-fructose-cholesterol (FFC) diet-induced murine NASH and during inflammation resolution by switching into a low-fat control diet. During NASH progression, protective effects were shown as HSC activation, cell infiltration and activation of pro-inflammatory macrophages were ameliorated. Furthermore, these changes were contrasted with the effects observed when neutrophil depletion was performed during the resolution phase. Impaired resolving mechanisms, such as a failure to balance the pro and anti-inflammatory cytokines ratio, deficient macrophage phenotypic switch into a pro-restorative profile, and defective repair and remodeling processes were observed when neutrophils were depleted in this scenario. This study described phase-dependent contrasting roles of neutrophils as triggers and pro-resolutive mediators of liver injury and fibrosis associated with diet-induced NASH in mice. These findings have important translational implications at the time of designing NASH therapeutic strategies.

COVID-19 Case Rates in Transitional Kindergarten Through Grade 12 Schools and in the Community - Los Angeles County, California, September 2020-March 2021.

In-person instruction during the COVID-19 pandemic concerns educators, unions, parents, students, and public health officials as they plan to create a safe and supportive learning environment for children and adolescents (1). Los Angeles County (LAC), the nation's largest county, has an estimated population of 10 million, including 1.7 million children and adolescents aged 5-17 years (2). LAC school districts moved to remote learning for some or all students in transitional kindergarten* through grade 12 (TK-12) schools during the 2020-21 school year (3). Schools that provided in-person instruction were required by LAC Health Officer orders to implement prevention measures such as symptom screening, masking, physical distancing, cohorting, and contact tracing (4). This analysis compares COVID-19 case rates in TK-12 schools among students and staff members who attended school in person with LAC case rates during September 2020-March 2021.

Levels of Trimethylamine N-Oxide Remain Elevated Long Term After Left Ventricular Assist Device and Heart Transplantation and Are Independent From Measures of Inflammation and Gut Dysbiosis.

BACKGROUND: Trimethylamine N-oxide (TMAO)-a gut-derived metabolite-is elevated in heart failure (HF) and linked to poor prognosis. We investigated variations in TMAO in HF, left ventricular assist device (LVAD), and heart transplant (HT) and assessed its relation with inflammation, endotoxemia, oxidative stress, and gut dysbiosis. METHODS: We enrolled 341 patients. TMAO, CRP (C-reactive protein), IL (interleukin)-6, TNF-α (tumor necrosis factor alpha), ET-1 (endothelin-1), adiponectin, lipopolysaccharide, soluble CD14, and isoprostane were measured in 611 blood samples in HF (New York Heart Association class I-IV) and at multiple time points post-LVAD and post-HT. Gut microbiota were assessed via 16S rRNA sequencing among 327 stool samples. Multivariable regression models were used to assess the relationship between TMAO and (1) New York Heart Association class; (2) pre- versus post-LVAD or post-HT; (3) biomarkers of inflammation, endotoxemia, oxidative stress, and microbial diversity. RESULTS: ln-TMAO was lower among HF New York Heart Association class I (1.23 [95% CI, 0.52-1.94] µM) versus either class II, III, or IV (1.99 [95% CI, 1.68-2.30], 1.97 [95% CI, 1.71-2.24], and 2.09 [95% CI, 1.83-2.34] µM, respectively; all P<0.05). In comparison to class II-IV, ln-TMAO was lower 1 month post-LVAD (1.58 [95% CI, 1.32-1.83] µM) and 1 week and 1 month post-HT (0.97 [95% CI, 0.60-1.35] and 1.36 [95% CI, 1.01-1.70] µM). ln-TMAO levels in long-term LVAD (>6 months: 1.99 [95% CI, 1.76-2.22] µM) and HT (>6 months: 1.86 [95% CI, 1.66-2.05] µM) were not different from symptomatic HF. After multivariable adjustments, TMAO was not associated with biomarkers of inflammation, endotoxemia, oxidative stress, or microbial diversity. CONCLUSIONS: TMAO levels are increased in symptomatic HF patients and remain elevated long term after LVAD and HT. TMAO levels were independent from measures of inflammation, endotoxemia, oxidative stress, and gut dysbiosis.