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.

Contribution of fatty acid oxidation to the pathogenesis of pulmonary hypertension.

Dysregulated metabolism characterizes both animal and human forms of pulmonary hypertension (PH). Enzymes involved in fatty acid metabolism have previously not been assessed in human pulmonary arteries affected by pulmonary arterial hypertension (PAH), and how inhibition of fatty acid oxidation (FAO) may attenuate PH remains unclear. Fatty acid metabolism gene transcription was quantified in laser-dissected pulmonary arteries from 10 explanted lungs with advanced PAH (5 idiopathic, 5 associated with systemic sclerosis), and 5 donors without lung diseases. Effects of oxfenicine, a FAO inhibitor, on female Sugen 5416-chronic hypoxia (SuHx) rats were studied in vivo using right heart catheterization, and ex vivo using perfused lungs and pulmonary artery ring segments. The impact of pharmacologic (oxfenicine) and genetic (carnitine palmitoyltransferase 1a heterozygosity) FAO suppression was additionally probed in mouse models of Schistosoma and hypoxia-induced PH. Potential mechanisms underlying FAO-induced PH pathogenesis were examined by quantifying ATP and mitochondrial mass in oxfenicine-treated SuHx pulmonary arterial cells, and by assessing pulmonary arterial macrophage infiltration with immunohistochemistry. We found upregulated pulmonary arterial transcription of 26 and 13 FAO genes in idiopathic and systemic sclerosis-associated PAH, respectively. In addition to promoting de-remodeling of pulmonary arteries in SuHx rats, oxfenicine attenuated endothelin-1-induced vasoconstriction. FAO inhibition also conferred modest benefit in the two mouse models of PH. Oxfenicine increased mitochondrial mass in cultured rat pulmonary arterial cells, and decreased the density of perivascular macrophage infiltration in pulmonary arteries of treated SuHx rats. In summary, FAO inhibition attenuated experimental PH, and may be beneficial in human PAH.

Circulating heparin oligosaccharides rapidly target the hippocampus in sepsis, potentially impacting cognitive functions.

Sepsis induces heparanase-mediated degradation of the endothelial glycocalyx, a heparan sulfate-enriched endovascular layer critical to vascular homeostasis, releasing highly sulfated domains of heparan sulfate into the circulation. These domains are oligosaccharides rich in heparin-like trisulfated disaccharide repeating units. Using a chemoenzymatic approach, an undecasaccharide containing a uniformly 13C-labeled internal 2-sulfoiduronic acid residue was synthesized on a p-nitrophenylglucuronide acceptor. Selective periodate cleavage afforded a heparin nonasaccharide having a natural structure. This 13C-labeled nonasaccharide was intravenously administered to septic (induced by cecal ligation and puncture, a model of polymicrobial peritonitis-induced sepsis) and nonseptic (sham) mice. Selected tissues and biological fluids from the mice were harvested at various time points over 4 hours, and the 13C-labeled nonasaccharide was recovered and digested with heparin lyases. The resulting 13C-labeled trisulfated disaccharide was quantified, without interference from endogenous mouse heparan sulfate/heparin, using liquid chromatography-mass spectrometry with sensitive and selective multiple reaction monitoring. The 13C-labeled heparin nonasaccharide appeared immediately in the blood and was rapidly cleared through the urine. Plasma nonasaccharide clearance was only slightly prolonged in septic mice (t1/2 ∼ 90 minutes). In septic mice, the nonasaccharide penetrated into the hippocampus but not the cortex of the brain; no hippocampal or cortical brain penetration occurred in sham mice. The results of this study suggest that circulating heparan sulfates are rapidly cleared from the plasma during sepsis and selectively penetrate the hippocampus, where they may have functional consequences.

Results from the post-exposure prophylaxis pilot program (P-QUAD) demonstration project in Los Angeles County.

Post-exposure prophylaxis (PEP) is a promising but under-utilized strategy for HIV prevention in high-risk populations. Between March 2010 and June 2011, two community-based clinics in Los Angeles County provided PEP in a pilot program to 267 unique individuals. Courses were primarily dispensed to men who have sex with men (84%) and consisted overwhelmingly of a three-drug antiretroviral therapy regimen containing two nucleoside reverse transcriptase inhibitors and either an integrase inhibitor (raltegravir) or a boosted protease inhibitor (lopinavir/ritonavir). Approximately 64% of all PEP courses were followed for at least 12 weeks, and seven individuals seroconverted. Of the seven seroconversions, six had subsequent re-exposure. The low rate of PEP failure calls for expanded funding for PEP in other jurisdictions.

Project Engage: Snowball Sampling and Direct Recruitment to Identify and Link Hard-to-Reach HIV-Infected Persons Who Are Out of Care.

INTRODUCTION: Innovative strategies are needed to identify and link hard-to-find persons living with HIV (PLWH) who are out of care (OOC). Project Engage, a health department-based project in Los Angeles County, used a mixed-methods approach to locate and provide linkage for PLWH who have limited contact with HIV medical and nonmedical services. METHODS: Incentivized social network recruitment (SNR) and direct recruitment (DR) was used to identify eligible OOC alters for a linkage intervention that included HIV clinic selection, appointment and transportation support, reminder calls/texts, and clinic navigation. RESULTS: Between 2012 and 2015, 112 alters were identified using SNR (n = 74) and DR (n = 38). Most alters were male (80%), African American (38%), and gay (60%). Sizable percentages were homeless (78%), had engaged in sex work (32%) in the previous 6 months, had injected drugs (47%), were incarcerated in the previous 12 months (50%), and had only received HIV care during the previous 5 years while incarcerated (24%). SNR alters were more likely than DR alters to be African American, uninsured, unemployed, homeless, sex workers, injection drug users, recently incarcerated, and have unmet service needs. Alters linked to care within 3 (69%), 4-6 (5%), and 7-12 months (8%), and 72% were retained at 6-12 months. The percent virally suppressed increased (27% vs. 41%) and the median viral load decreased (P = 0.003) between linkage and follow-up at 6-12 months. DISCUSSION: The alternative approaches presented were effective at locating marginalized HIV-positive persons who are OOC for linkage and retention. The SNR approach was most successful at identifying alters with serious social challenges and gaps in needed medical/ancillary services.

Methods to Obtain a Representative Sample of Ryan White-Funded Patients for a Needs Assessment in Los Angeles County: Results from a Replicable Approach.

The Health Resources and Services Administration requires that jurisdictions receiving Ryan White (RW) funding justify need, set priorities, and provide allocations using evidence-based methods. Methods and results from the 2011 Los Angeles Coordinated HIV/AIDS Needs Assessment-Care (LACHNA-Care) study are presented. Individual-level weights were applied to expand the sample from 400 to 18 912 persons, consistent with the 19 915 clients in the system. Awareness, need, and utilization for medical outpatient care were high (>90%). Other services (eg, child care) had limited awareness (21%). Majority of participants reported at least 1 service gap (81%). Lack of insurance (risk ratio [RR] = 3.0, 95% confidence interval [CI]: 1.5-6.2), substance use (RR = 2.9, 95% CI: 1.3-6.4), and past lapses in medical care (RR = 2.8, 95% CI: 1.3-5.9) were associated with gaps. Within clusters, past incarceration was associated with gaps for housing (RR = 13.5, 95% CI: 3.5-52.1), transportation (RR = 3.2, 95% CI: 1.2-8.4), and case management (RR = 4.0, 95% CI: 1.3-12.2). Applied methods resulted in representative data instrumental to RW program planning efforts.

RTP801 Amplifies Nicotinamide Adenine Dinucleotide Phosphate Oxidase-4-Dependent Oxidative Stress Induced by Cigarette Smoke.

Tobacco smoke (TS) causes chronic obstructive pulmonary disease, including chronic bronchitis, emphysema, and asthma. Rtp801, an inhibitor of mechanistic target of rapamycin, is induced by oxidative stress triggered by TS. Its up-regulation drives lung susceptibility to TS injury by enhancing inflammation and alveolar destruction. We postulated that Rtp801 is not only increased by reactive oxygen species (ROS) in TS but also instrumental in creating a feedforward process leading to amplification of endogenous ROS generation. We used cigarette smoke extract (CSE) to model the effect of TS in wild-type (Wt) and knockout (KO-Rtp801) mouse lung fibroblasts (MLF). The production of superoxide anion in KO-Rtp801 MLF was lower than that in Rtp801 Wt cells after CSE treatment, and it was inhibited in Wt MLF by silencing nicotinamide adenine dinucleotide phosphate oxidase-4 (Nox4) expression with small interfering Nox4 RNA. We observed a cytoplasmic location of ROS formation by real-time redox changes using reduction-oxidation-sensitive green fluorescent protein profluorescent probes. Both the superoxide production and the increase in the cytoplasmic redox were inhibited by apocynin. Reduction in the activity of Sod and decreases in the expression of Sod2 and Gpx1 genes were associated with Rtp801 CSE induction. The ROS produced by Nox4 in conjunction with the decrease in cellular antioxidant enzymatic defenses may account for the observed cytoplasmic redox changes and cellular damage caused by TS.

Implementation and Operational Research: The Navigation Program: An Intervention to Reengage Lost Patients at 7 HIV Clinics in Los Angeles County, 2012-2014.

The Navigation Program is a health department-community agency collaboration to reengage lost HIV clinic patients in Los Angeles County using best practices from disease investigator services locator activities and the Antiretroviral Treatment Access Study (ARTAS), a CDC-recommended intervention. Clinic databases were reviewed to identify HIV patients who: (1) had no HIV care visits in 6-12 months and last viral load was greater than 200 copies per milliliter; (2) had no HIV care visits in >12 months; (3) were newly diagnosed and never in care; or (4) were recently released from jail/prison/other institution with no regular HIV medical provider. Patients were contacted by trained Navigators using locator information from clinic medical records, HIV/sexually transmitted disease surveillance, and people-finder databases and offered enrollment in a modified ARTAS intervention. Among the 1139 lost clinic patients identified, 36% were in care elsewhere, 29% could not be located, 8% returned to the clinic independently, 4% declined enrollment, and 7% (n = 78) were located and enrolled in the intervention. Participants received an average of 4.5 Navigator sessions over 11.6 hours. Among reengaged patients, 68% linked within 3 months, 85% linked within 6 months, and 94% linked within 12 months, and 82% of linked patients were retained in care 12 months after study enrollment. The percentage of linked patients virally suppressed was compared at time of linkage by the Navigators (52%) with a second viral load measure after linkage to care (63%) (χ(2) = 11.8; P = 0.01). The combined disease investigator services/ARTAS model of reengagement was effective for locating and reengaging lost HIV clinic patients. Access to HIV surveillance data is critical for the efficient identification of persons truly in need of reengagement.

Adaptation of the HIV Care Continuum as a Method for Evaluating Syphilis and Gonorrhea Disease Control Activities in Los Angeles County.

BACKGROUND: Treatment verification and contact elicitation are core approaches used to control the spread of sexually transmitted diseases (STDs). Methodology adapted from the HIV care continuum is presented as an evaluation and communication tool for STD control activities. METHODS: Sexually transmitted disease surveillance and program data for Los Angeles County in 2013 were used to construct a 2-part continuum to examine syphilis (all stages) and gonorrhea outcomes among index patients and elicited contacts. The Index Case Continuum (Part 1) assesses the proportion of patients who were treated, assigned for interview, interviewed, and provided name and locating information for at least 1 contact. The Elicited Contact Continuum (Part 2) assesses the proportion of contacts who were located, interviewed, and treated. RESULTS: Among 3668 patients with syphilis, 97% (n = 3556) were treated, 72% (n = 2633) were interviewed, and 25% (n = 920) provided name and locating information for at least 1 contact. The corresponding numbers for 12,541 gonorrhea cases were 95% (n = 11,936), 45% (n = 5633), and 16% (1944), respectively. Among the 1392 contacts elicited from syphilis cases, 53% (n = 735) were either interviewed or determined to not need an interview and 43% (n = 595) were treated. The corresponding numbers for the 2323 contacts elicited from gonorrhea cases were 53% (n = 1221) and 46% (n = 1075), respectively. CONCLUSIONS: Adaptation of the HIV continuum is a useful tool for evaluating treatment verification and contact elicitation activities. In Los Angeles County, this approach revealed significant drop-offs in the proportion of index cases naming contacts and in the proportion of contacts who are interviewed and treated.

Novosphingobium and its potential role in chronic obstructive pulmonary diseases: insights from microbiome studies.

Bacterial infection of lung airways underlies some of the main complications of COPD, significantly impacting disease progression and outcome. Colonization by bacteria may further synergize, amplify, or trigger pathways of tissue damage started by cigarette smoke, contributing to the characteristic airway inflammation and alveolar destruction of COPD. We sought to elucidate the presence and types of lung bacterial populations in different stages of COPD, aimed at revealing important insights into the pathobiology of the disease. Sequencing of the bacterial small subunit ribosomal RNA gene in 55 well-characterized clinical lung samples, revealed the presence of Novosphingobium spp. (>2% abundance) in lungs of patients with GOLD 3-GOLD 4 COPD, cystic fibrosis and a subset of control individuals. Novosphingobium-specific quantitative PCR was concordant with the sequence data and high levels of Novosphingobium spp. were quantifiable in advanced COPD, but not from other disease stages. Using a mouse model of subacute lung injury due to inhalation of cigarette smoke, bronchoalveolar lavage neutrophil and macrophage counts were significantly higher in mice challenged intratracheally with N. panipatense compared to control mice (p<0.01). Frequencies of neutrophils and macrophages in lung tissue were increased in mice challenged with N. panipatense at room air compared to controls. However, we did not observe an interaction between N. panipatense and subacute cigarette smoke exposure in the mouse. In conclusion, Novosphingobium spp. are present in more severe COPD disease, and increase inflammation in a mouse model of smoke exposure.

Rtp801 suppression of epithelial mTORC1 augments endotoxin-induced lung inflammation.

The mechanistic target of rapamycin (mTOR) is a central regulator of cellular responses to environmental stress. mTOR (and its primary complex mTORC1) is, therefore, ideally positioned to regulate lung inflammatory responses to an environmental insult, a function directly relevant to disease states such as the acute respiratory distress syndrome. Our previous work in cigarette smoke-induced emphysema identified a novel protective role of pulmonary mTORC1 signaling. However, studies of the impact of mTORC1 on the development of acute lung injury are conflicting. We hypothesized that Rtp801, an endogenous inhibitor of mTORC1, which is predominantly expressed in alveolar type II epithelial cells, is activated during endotoxin-induced lung injury and functions to suppress anti-inflammatory epithelial mTORC1 responses. We administered intratracheal lipopolysaccharide to wild-type mice and observed a significant increase in lung Rtp801 mRNA. In lipopolysaccharide-treated Rtp801(-/-) mice, epithelial mTORC1 activation significantly increased and was associated with an attenuation of lung inflammation. We reversed the anti-inflammatory phenotype of Rtp801(-/-) mice with the mTORC1 inhibitor, rapamycin, reassuring against mTORC1-independent effects of Rtp801. We confirmed the proinflammatory effects of Rtp801 by generating a transgenic Rtp801 overexpressing mouse, which displayed augmented inflammatory responses to intratracheal endotoxin. These data suggest that epithelial mTORC1 activity plays a protective role against lung injury, and its inhibition by Rtp801 exacerbates alveolar injury caused by endotoxin.

Heparanase mediates renal dysfunction during early sepsis in mice.

Heparanase, a heparan sulfate-specific glucuronidase, mediates the onset of pulmonary neutrophil adhesion and inflammatory lung injury during early sepsis. We hypothesized that glomerular heparanase is similarly activated during sepsis and contributes to septic acute kidney injury (AKI). We induced polymicrobial sepsis in mice using cecal ligation and puncture (CLP) in the presence or absence of competitive heparanase inhibitors (heparin or nonanticoagulant N-desulfated re-N-acetylated heparin [NAH]). Four hours after surgery, we collected serum and urine for measurement of renal function and systemic inflammation, invasively determined systemic hemodynamics, harvested kidneys for histology/protein/mRNA, and/or measured glomerular filtration by inulin clearance. CLP-treated mice demonstrated early activation of glomerular heparanase with coincident loss of glomerular filtration, as indicated by a >twofold increase in blood urea nitrogen (BUN) and a >50% decrease in inulin clearance (P < 0.05) in comparison to sham mice. Administration of heparanase inhibitors 2 h prior to CLP attenuated sepsis-induced loss of glomerular filtration rate, demonstrating that heparanase activation contributes to early septic renal dysfunction. Glomerular heparanase activation was not associated with renal neutrophil influx or altered vascular permeability, in marked contrast to previously described effects of pulmonary heparanase on neutrophilic lung injury during sepsis. CLP induction of renal inflammatory gene (IL-6, TNF-α, IL-1ß) expression was attenuated by NAH pretreatment. While serum inflammatory indices (KC, IL-6, TNF-α, IL-1ß) were not impacted by NAH pretreatment, heparanase inhibition attenuated the CLP-induced increase in serum IL-10. These findings demonstrate that glomerular heparanase is active during sepsis and contributes to septic renal dysfunction via mechanisms disparate from heparanase-mediated lung injury.

The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis.

Sepsis, a systemic inflammatory response to infection, commonly progresses to acute lung injury (ALI), an inflammatory lung disease with high morbidity. We postulated that sepsis-associated ALI is initiated by degradation of the pulmonary endothelial glycocalyx, leading to neutrophil adherence and inflammation. Using intravital microscopy, we found that endotoxemia in mice rapidly induced pulmonary microvascular glycocalyx degradation via tumor necrosis factor-α (TNF-α)-dependent mechanisms. Glycocalyx degradation involved the specific loss of heparan sulfate and coincided with activation of endothelial heparanase, a TNF-α-responsive, heparan sulfate-specific glucuronidase. Glycocalyx degradation increased the availability of endothelial surface adhesion molecules to circulating microspheres and contributed to neutrophil adhesion. Heparanase inhibition prevented endotoxemia-associated glycocalyx loss and neutrophil adhesion and, accordingly, attenuated sepsis-induced ALI and mortality in mice. These findings are potentially relevant to human disease, as sepsis-associated respiratory failure in humans was associated with higher plasma heparan sulfate degradation activity; moreover, heparanase content was higher in human lung biopsies showing diffuse alveolar damage than in normal human lung tissue.

Mercado, Organización e innovación: Cobertura de seguro / Market, Organization and innovation: Coverage of assurance

El fin último de cualquier sistema de salud es contribuir a la mejora de la salud de la población y hacerlo de la manera más eficiente posible, Buscando mejorar las condiciones de eficiencia y equidad en que se prestan los servicios de salud, numerosos países en todo el mundo, incluyendo los latinoamericanos, han implementado reformas. A pesar de la aparene coincidencia en los objetivos de las reformas, la modalidad en que se implementan responde a conceptos y valores diferentes. En este trabajo analizamos los valores, igualiarios, subyacentes en los distintos conceptos de equidad. A partir de ellos desarrollamos criterios que nos permitan interpretar algunas de las estrategias, financiamiento y prestación de los servicios de salud aplicados por las reformas de los sistemas de salud en la Provincia de Misiones. Estos criterios son aplicados a las políticas de financiamiento y prestacionesde las reformas aplicadas en los sistemas de salud concretado en un seguro de salud.

Hepatitis and human immunodeficiency virus co-infection among injection drug users in Los Angeles County, California.

This study examined the prevalence of hepatitis A (HAV), B (HBV), C (HCV), and Human Immunodeficiency Virus (HIV) co-infection among Injection Drug Users (IDUs) in Los Angeles County, California, and predictors of multiple infections in this population. Six hundred seventy-nine IDUs were recruited from October 2002 through June 2004. Participants completed questionnaires to elicit demographic, drug and sex risk information, and were tested for hepatitis A, B, C and HIV.A linear regression model predicting the total number of infections (0 to 4 possible) was constructed. Significant associations were found between HAV and HBV infection, HAV and HCV infection, and HBV and HCV infection. Predictors of total co-infections included age of first injection, lifetime years in jail, and Hispanic ethnicity. Latinos had the highest proportion of HAV and HBV co-infection with HCV. The total number of co-infections, especially those co-infected with all three of the hepatitis infections, was unexpectedly high.