Sexual Exposures Associated With Mpox Infection: California, November 2022 to June 2023.

BACKGROUND: Exposures associated with mpox infection remain imperfectly understood. METHODS: We conducted a case-control study enrolling participants who received molecular tests for mpox/orthopoxvirus in California from November 2022 through June 2023. We collected data on behaviors during a 21-day risk period before symptom onset or testing among mpox case patients and test-negative controls. RESULTS: Thirteen of 54 case patients (24.1%) and 5 of 117 controls (4.3%) reported sexual exposure to individuals they identified as potential mpox case patients ("index contacts"; odds ratio [OR], 7.7 [95% confidence interval (CI), 2.5-19.3] relative to individuals who did not report exposure to potential mpox case patients). Among these participants, 10 of 13 case patients (76.9%) and 2 of 5 controls (40.0%) reported that their index contacts were not experiencing symptoms visible to participants during sex (OR, 14.9 [95% CI, 3.6-101.8]). Only 3 of 54 case patients (5.6%) reported exposure to symptomatic index contacts. Case patients reported more anal/vaginal sex partners than did controls (adjusted OR, 2.2 [95% CI, 1.0-4.8] for 2-3 partners and 3.8 [1.7-8.8] for ≥4 partners). Male case patients with penile lesions more commonly reported insertive anal/vaginal sex than those without penile lesions (adjusted OR, 9.3 [95% CI, 1.6-54.8]). Case patients with anorectal lesions more commonly reported receptive anal sex than those without anorectal lesions (adjusted OR, 14.4 [95% CI, 1.0-207.3]). CONCLUSIONS: Sexual exposure to contacts known or suspected to have experienced mpox was associated with increased risk of infection, often when index contacts lacked apparent symptoms. Exposure to more sex partners, including those whom participants did not identify as index contacts, was associated with increased risk of infection in a site-specific manner. While participants' assessment of symptoms in partners may be imperfect, these findings suggest that individuals without visibly prominent mpox symptoms transmit infection.

Comparing 7-Day Versus 6-8-Day Penicillin Treatment Intervals Among Pregnant People With Syphilis of Late or Unknown Duration: No Difference Found in Incidence of Congenital Syphilis.

Background: Guidelines recommend that pregnant patients with syphilis of late/unknown duration be treated with benzathine penicillin G, dosed as 3 weekly intramuscular injections (BPGx3) given ideally at strict 7-day intervals. Given limited pharmacokinetic data, it is unknown whether more flexible BPG treatment intervals might be effective in preventing congenital syphilis (CS). Methods: We used California surveillance data to identify birthing parent/infant dyads wherein the pregnant parent had syphilis of late/unknown duration between January 1, 2016 - June 30, 2019. We divided the dyads into 3 groups based on prenatal treatment: (1) BPGx3 at strict 7-day intervals, (2) BPGx3 at 6-8 day intervals, and (3) no/inadequate treatment. We then compared CS incidence among infants in each group. Results: We analyzed 1,092 parent/infant dyads: 607 (55.6%) in the 7-day treatment group, 70 (6.4%) in the 6-8 day treatment group, and 415 (38.0%) in the no/inadequate treatment group. The incidence proportion of infants meeting CS criteria in each group was, respectively, 5.6%, 5.7%, and 36.9%. Compared with BPGx3 at 7-day intervals, the odds of CS were 1.0 [95% CI 0.4-3.0] in the 6-8 day group and 9.8 [95% CI 6.6-14.7] in the no/inadequate treatment group. Conclusions: Prenatal BPGx3 at 6-8 days was no more likely to lead to CS in infants than 7-days. These findings hint that 6-8-day intervals might be adequate to prevent CS among pregnant people with syphilis of late/unknown duration. Consequently, it is possible that CS evaluation beyond an RPR at delivery may be unnecessary in asymptomatic infants whose parents received BPGx3 at 6-8 days.

Characterizing the Rise of Disseminated Gonococcal Infections in California, July 2020-July 2021.

BACKGROUND: California has experienced an increase in reported cases of disseminated gonococcal infection (DGI). Given significant morbidity associated with DGI and the ability of Neisseria gonorrhoeae to rapidly develop antibiotic resistance, characterization of these cases can inform diagnosis, management, and prevention of DGI. METHODS: As part of the public health response to increased reports of DGI, we used gonorrhea surveillance data reported to the California Department of Public Health to identify all DGI cases in a geographically-bound region. Standardized case report forms were used to collect epidemiologic risk factors and clinical information obtained from provider/laboratory reports, medical records, and patient interviews. RESULTS: From 1 July 2020 to 31 July 2021, we identified 149 DGI patients among 63 338 total gonorrhea infections, representing 0.24% of gonorrhea cases. Estimated incidence was 0.47 DGI cases per 100 000 person-years. Mean age of DGI patients was 40 years, and 75 (50%) were cisgender men, of whom only 13 were known to have male partners. Where reported, more than one-third (36%) used methamphetamine and nearly one-quarter (23%) experienced homelessness. Clinically, 61% lacked urogenital, pharyngeal, or rectal symptoms; 2 patients died in the hospital. Among 47 isolates from patients with antimicrobial susceptibility testing (AST) results available, all were susceptible to ceftriaxone and cefixime. CONCLUSIONS: Most DGI patients lacked urogenital symptoms and were not among populations for which routine gonorrhea screening is currently recommended. Expanding gonorrhea screening might prevent DGI. Cefixime is likely the best option if transitioning from parenteral to oral therapy when AST results are unavailable.

Congenital syphilis prevention in the context of methamphetamine use and homelessness.

BACKGROUND AND OBJECTIVES: Congenital syphilis (CS) is increasing in the United States and is associated with intersecting social and structural determinants of health. This study aimed to delineate birthing parent characteristics associated with CS in an adjusted model. METHODS (N = 720): People diagnosed with syphilis during pregnancy from 2017 to 2018 who were interviewed and linked to infants in the California state surveillance system were included (herein, "birthing parents"). Sociodemographic and clinical CS risk factors informed a stepwise multivariable logistic regression model in which the outcome of interest was infants born with CS. CS prevention continuums delineated the proportion of pregnant people with syphilis who completed steps (e.g., prenatal care entry, syphilis testing, treatment) needed to prevent CS; the outcome was delivering an infant without CS. We stratified continuums by homelessness and methamphetamine use to explore differences in CS outcomes. RESULTS: Of 720 birthing parents, 245 (34%) delivered an infant with CS. Although CS was initially associated with homelessness (odds ratio [OR] = 2.5, 95% confidence interval [CI]: 1.6, 4.0) and methamphetamine use (OR = 2.1, 95% CI: 1.4, 3.1), the addition of prenatal care into a final adjusted model attenuated these associations to not significant. In CS prevention continuums, delivering an infant without CS was less likely for people who reported methamphetamine use (p < .001) and/or homelessness (p < .001). However, when examining only those who received prenatal care, statistical differences for these predictors no longer existed. In the final adjusted model the following were associated with CS: no prenatal care (OR = 16.7, 95% CI: 9.2, 30.3) or late prenatal care (OR = 2.9, 95% CI: 1.9, 4.2); early stage of syphilis (OR = 2.6, 95% CI: 1.8, 3.7); living in Central California (OR = 2.1, 95% CI: 1.1, 4.2). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: This is the first analysis to explore birthing parent characteristics associated with delivering an infant with CS in an adjusted model. We demonstrate that prenatal care, when accessed, can result in effective CS prevention among people who are unhoused and/or using methamphetamine equally well compared to counterparts without these risk factors.

Trends in HIV prevalence by self-report among MSM diagnosed and reported with gonorrhea in six United States jurisdictions from 2010 to 2019.

BACKGROUND: HIV co-infection among persons diagnosed with gonorrhea is not well characterized. Trends in HIV prevalence among persons diagnosed with gonorrhea may have significant implications for HIV prevention interventions, especially for MSM. MSM are increasingly and disproportionately represented among incident gonorrhea cases reported in a multistate sentinel surveillance network. Using data from this network, we estimated HIV prevalence among MSM by self-report and explored trends in co-infection by key demographics. DESIGN: Observational study using enhanced surveillance data. METHODS: Six geographically diverse jurisdictions in the STD Surveillance Network (SSuN) 2010-2019 randomly sampled laboratory-confirmed gonorrhea cases. Enhanced investigations on sampled cases included patient interviews eliciting demographic, behavioral and HIV testing history. These data were weighted to adjust for study design and nonresponse to estimate trends in HIV prevalence. RESULTS: Of 653 522 reported cases, 28 979 were sampled and investigated. The proportion of cases reporting living with diagnosed HIV at the time of their gonorrhea diagnosis increased 61% across the study period from 6.6% in 2010 to 10.8% in 2019. The observed increase in HIV prevalence is concurrent with an increase in the proportion of gonorrhea cases attributable to MSM. HIV prevalence among MSM decreased in two jurisdictions and increasing trends were observed among non-Hispanic Black and Hispanic MSM. HIV prevalence decreased among non-Hispanic white MSM, MSM under 20 and those 40 years of age or older. CONCLUSION: Diagnosis with gonorrhea, especially among MSM, should be a sentinel event triggering screening for HIV, referral to high-impact HIV prevention interventions or to HIV primary care.

Neurosyphilis Surveillance: Exploring the Use of Multiple Data Sources to Better Understand Morbidity in California.

ABSTRACT: Accurate reporting of neurosyphilis diagnoses is important to quantify and monitor severe outcomes associated with infection of Treponemal pallidum. This analysis compared the demographic distribution of neurosyphilis diagnoses in sexually transmitted disease surveillance data with administrative hospital data in the California Project Area from 2016 to 2018. Although neurosyphilis morbidity was similar, significant differences were noted by sex, age group, race/ethnicity, and region. Both sexually transmitted disease surveillance and administrative hospital data may be imperfect systems to understand the true morbidity of neurosyphilis.

Measuring the Impact of the COVID-19 Pandemic on Sexually Transmitted Diseases Public Health Surveillance and Program Operations in the State of California.

BACKGROUND: As public health personnel and resources are redirected to COVID-19, sexually transmitted diseases (STD) programs have been unable to sustain pre-COVID-19 activities. METHODS: We used California (CA) surveillance data to describe trends in case reporting for gonorrhea, chlamydia, and syphilis of any stage in the pre- versus post-COVID-19 eras (January-June 2019 and January-June 2020). We also analyzed data from an electronic survey administered by the CA STD Control Branch to local health jurisdictions in April, June, and September of 2020, assessing the impact of COVID-19 on STD programs. RESULTS: There were sharp declines in cases of all reportable bacterial STDs occurring in conjunction with the March 19, 2020 CA stay-at-home order, most of which did not return to baseline by July. Comparing January-June 2020 to January-June of 2019, there were decreases in reported cases of chlamydia (31%), late syphilis (19%), primary/secondary syphilis (15%), early nonprimary nonsecondary syphilis (14%), and gonorrhea (13%). The largest percentage declines in STD case reporting were among Hispanic, Asian/Pacific Islander, and Black persons. Seventy-eight percent of local health jurisdiction respondents indicated that half or more of their workforce had been redeployed to COVID-19 by September 2020. CONCLUSIONS: During the COVID-19 era, STD case reporting and programmatic functions have diminished throughout CA. Because this may contribute to decreases or delays in STD diagnosis and treatment-with resultant increases in STD transmission-providers and public health officials should prepare for potential increases in STD-related morbidity in the months and years to come.

Routine Screening in a California Jail : Effect of Local Policy on Identification of Syphilis in a High-Incidence Area, 2016-2017.

OBJECTIVES: California is experiencing a syphilis and congenital syphilis epidemic, and many persons diagnosed with syphilis report a history of recent incarceration or sexual contact with a person who has recently been incarcerated. Fresno County's local health department and jail collaborated to implement a routine syphilis screening policy for male adults aged 18-30 and female adults aged 18-35 booked into the facility. We evaluated syphilis screening, case finding, and treatment rates after implementation of the new policy. METHODS: We linked jail census and laboratory data to syphilis surveillance data to assess screening coverage, positivity, and treatment rates for age-eligible persons who were booked into Fresno County Jail from April 1, 2016, through December 31, 2017. RESULTS: Of 24 045 age-eligible persons who were booked into the jail during the study period, 5897 (24.5%) were female and 18 148 (75.5%) were male. Of 7144 (29.7%) persons who were screened for syphilis, 611 (8.6%) had a reactive rapid plasma reagin blood test result (16.4% [253 of 1546] of female adults; 6.4% [358 of 5598] of male adults) and 238 (3.3%) were newly diagnosed with syphilis, as confirmed by matching to the surveillance system (6.9% [106 of 1546] of female adults; 2.4% [132 of 5598] of male adults). Of persons identified with syphilis, 51.7% (n = 123 of 238) received adequate recommended treatment (59.4% [63 of 106] of female adults; 45.5% [60 of 132] of male adults). CONCLUSIONS: The age-based syphilis screening policy adopted in this jail yielded high positivity, including newly identified syphilis infections among female adults of childbearing age. The targeted screening policy was formalized in the county-negotiated contract with the jail's private correctional health care company in 2018-a strategy that can be replicated.

Molecular Basis for Ser/Thr Specificity in PKA Signaling.

cAMP-dependent protein kinase (PKA) is the major receptor of the second messenger cAMP and a prototype for Ser/Thr-specific protein kinases. Although PKA strongly prefers serine over threonine substrates, little is known about the molecular basis of this substrate specificity. We employ classical enzyme kinetics and a surface plasmon resonance (SPR)-based method to analyze each step of the kinase reaction. In the absence of divalent metal ions and nucleotides, PKA binds serine (PKS) and threonine (PKT) substrates, derived from the heat-stable protein kinase inhibitor (PKI), with similar affinities. However, in the presence of metal ions and adenine nucleotides, the Michaelis complex for PKT is unstable. PKA phosphorylates PKT with a higher turnover due to a faster dissociation of the product complex. Thus, threonine substrates are not necessarily poor substrates of PKA. Mutation of the DFG+1 phenylalanine to ß-branched amino acids increases the catalytic efficiency of PKA for a threonine peptide substrate up to 200-fold. The PKA Cα mutant F187V forms a stable Michaelis complex with PKT and shows no preference for serine versus threonine substrates. Disease-associated mutations of the DFG+1 position in other protein kinases underline the importance of substrate specificity for keeping signaling pathways segregated and precisely regulated.

Divalent metal ions control activity and inhibition of protein kinases.

Protein kinases are key enzymes in the regulation of eukaryotic signal transduction. As metalloenzymes they employ divalent cations for catalysis and regulation. We used the catalytic (C) subunit of cAMP-dependent protein kinase (PKA) as a model protein to investigate the role of a variety of physiologically or pathophysiologically relevant divalent metal ions in distinct steps within the catalytic cycle. It is established that divalent metal ions play a crucial role in co-binding of nucleotides and also assist in catalysis. Our studies reveal that besides the physiologically highly relevant magnesium, metals like zinc and manganese can assist in phosphoryl transfer, however, only a few support efficient substrate turnover (turnover catalysis). Those trace metals allow for substrate binding and phosphotransfer but hamper product release. We further established the unique role of magnesium as the common biologically relevant divalent metal ideally enabling (co-) substrate binding and orientation. Magnesium allows stable substrate binding and, on the other hand accelerates product release, thus being extremely efficient in turnover catalysis. We extended our studies to non-catalytic functions of protein kinases looking at pseudokinases, a subfamily of protein kinases inherently lacking critical residues for catalysis. Recently, pseudokinases have been linked to human diseases. Some pseudokinases are still capable of binding metal ions, yet have lost the ability to transfer the phosphoryl group from ATP to a given substrate. Here metal ions stabilize an active like, though catalytically unproductive conformation and are therefore crucial to maintain non-catalytic function. Finally, we demonstrate for the canonical kinase PKA that the trace metal manganese alone can stabilize protein kinases in an active like conformation allowing them to bind substrates even in the absence of nucleotides.

Trends in Chlamydia Screening, Test Positivity, and Treatment Among Females in California Juvenile Detention Facilities, 2003-2014.

BACKGROUND: Juvenile detention facilities house adolescents at high risk for sexually transmitted diseases. Collaboration between health departments and juvenile detention authorities can provide routine, cost-efficient chlamydia screening and treatment to females with limited access to care. We describe trends in screening, positivity, treatment, and associated costs in a well-established juvenile detention chlamydia screening program. METHODS: In the California Chlamydia Screening Project, juvenile detention facilities in 12 counties collected quarterly aggregate data on female census and line-listed chlamydia test results and treatment data from fiscal year (FY) 2003-2004 to FY 2013-2014. Trends in the proportion of females screened, positivity, and treatment by age, race/ethnicity, and facility volume were evaluated by Cochran-Armitage test. The median cost of the program per chlamydia positive identified was compared by facility in FY 2013-2014. RESULTS: Data from 59,518 test records among juvenile females indicated high screening rates (75.1%-79.4%). Chlamydia positivity, although consistently high, decreased from 14.8% in 2003-2004 to 11.5% in 2013-2014 (P < 0.001). Documented treatment decreased (88.8% in 2005-2006 to 79.0% in 2013-2014, P < 0.001); of those treated, treatment within 7 days increased (80.1% in 2005-2006 to 88.8% in 2013-2014, P < 0.001). The median cost per chlamydia positive identified was $708 (interquartile range, $669-$894) and was lowest for facilities with high chlamydia positivity. CONCLUSIONS: The California Chlamydia Screening Project demonstrated consistently high rates of chlamydia screening and positivity among adolescent females while keeping costs low for high-volume facilities. Further improvement in timely treatment rates remains a challenge for extending the impact of screening in this high-risk population.

Patient-Reported Expedited Partner Therapy for Gonorrhea in the United States: Findings of the STD Surveillance Network 2010-2012.

BACKGROUND: Expedited partner therapy (EPT) has been shown to prevent reinfection in persons with gonorrhea and to plausibly reduce incidence. The Centers for Disease Control and Prevention recommends EPT as an option for treating sex partners of heterosexual patients. Few studies that examine how the reported use of this valuable intervention differs by patient and provider characteristics and by geography across multiple jurisdictions in the United States are currently available. METHODS: Case and patient interview data were obtained for a random sample of reported cases from 7 geographically disparate US jurisdictions participating in the Sexually Transmitted Disease (STD) Surveillance Network. These data were weighted to be representative of all reported gonorrhea cases in the 7 study sites. Patient receipt of EPT was estimated, and multivariate models were constructed separately to examine factors associated with receipt of EPT for heterosexuals and for men who have sex with men. RESULTS: Overall, 5.4% of patients diagnosed and reported as having gonorrhea reported receiving EPT to treat their sex partners. Heterosexual patients were more likely to have received EPT than men who have sex with men at 6.6% and 2.6% of patients, respectively. Receipt of EPT did not vary significantly by race, Hispanic ethnicity, or age for either group, although significant variation was observed in different provider settings, with patients from family planning/reproductive health and STD clinic settings more likely to report receiving EPT. Jurisdiction variations were also observed with heterosexual patients in Washington State most likely (35.5%), and those in New York City, Connecticut, and Philadelphia least likely to report receiving EPT (<2%). CONCLUSIONS: With the exception of one jurisdiction in the STD Surveillance Network actively promoting EPT use, patient-reported receipt of the intervention remains suboptimal across the network. Additional efforts to promote EPT, especially for patients diagnosed in private provider and hospital settings, are needed to realize the full potential of this valuable gonorrhea control intervention.

Divalent Metal Ions Mg²âº and Ca²âº Have Distinct Effects on Protein Kinase A Activity and Regulation.

cAMP-dependent protein kinase (PKA) is regulated primarily in response to physiological signals while nucleotides and metals may provide fine-tuning. PKA can use different metal ions for phosphoryl transfer, yet some, like Ca(2+), do not support steady-state catalysis. Fluorescence Polarization (FP) and Surface Plasmon Resonance (SPR) were used to study inhibitor and substrate interactions with PKA. The data illustrate how metals can act differentially as a result of their inherent coordination properties. We found that Ca(2+), in contrast to Mg(2+), does not induce high-affinity binding of PKA to pseudosubstrate inhibitors. However, Ca(2+) works in a single turnover mode to allow for phosphoryl-transfer. Using a novel SPR approach, we were able to directly monitor the interaction of PKA with a substrate in the presence of Mg(2+)ATP. This allows us to depict the entire kinase reaction including complex formation as well as release of the phosphorylated substrate. In contrast to Mg(2+), Ca(2+) apparently slows down the enzymatic reaction. A focus on individual reaction steps revealed that Ca(2+) is not as efficient as Mg(2+) in stabilizing the enzyme:substrate complex. The opposite holds true for product dissociation where Mg(2+) easily releases the phospho-substrate while Ca(2+) traps both reaction products at the active site. This explains the low steady-state activity in the presence of Ca(2+). Furthermore, Ca(2+) is able to modulate kinase activity as well as inhibitor binding even in the presence of Mg(2+). We therefore hypothesize that the physiological metal ions Mg(2+) and Ca(2+) both play a role in kinase activity and regulation. Since PKA is localized close to calcium channels and may render PKA activity susceptible to Ca(2+), our data provide a possible mechanism for novel crosstalk between cAMP and calcium signaling.

Systematic interpretation of cyclic nucleotide binding studies using KinetXBase.

Functional proteomics aims to describe cellular protein networks in depth based on the quantification of molecular interactions. In order to study the interaction of adenosine-3',5'-cyclic monophosphate (cAMP), a general second messenger involved in several intracellular signalling networks, with one of its respective target proteins, the regulatory (R) subunit of cAMP dependent protein kinase (PKA), a number of different methods was employed. These include fluorescence polarisation (FP), isothermal titration calorimetry (ITC), surface plasmon resonance (SPR), amplified luminescence proximity homogeneous assay (ALPHA-screen), radioligand binding or activity-based assays. Kinetic, thermodynamic and equilibrium binding data of a variety of cAMP derivatives to several cAMP binding domains were integrated in a single database system, we called KinetXBase, allowing for very distinct data formats. KinetXBase is a practical data handling system for molecular interaction data of any kind, providing a synopsis of data derived from different technologies. This supports ongoing efforts in the bioinformatics community to devise formal concepts for a unified representation of interaction data, in order to enable their exchange and easy comparison. KinetXBase was applied here to analyse complex cAMP binding data and highly site-specific cAMP analogues could be identified. The software package is free for download by academic users.