To understand the roles of acute-phase viral dynamics and host immune responses in post-acute sequelae of SARS-CoV-2 infection (PASC), we enrolled 136 participants within 5 days of their first positive SARS-CoV-2 real-time PCR test. Participants self-collected up to 21 nasal specimens within the first 28 days post-symptom onset; interviewer-administered questionnaires and blood samples were collected at enrollment, days 9, 14, 21, 28, and month 4 and 8 post-symptom onset. Defining PASC as the presence of any COVID-associated symptom at their 4-month visit, we compared viral markers (quantity and duration of nasal viral RNA load, infectious viral load, and plasma N-antigen level) and host immune markers (IL-6, IL-10, TNF-α, IFN-α, IFN-γ, MCP, IP-10, and Spike IgG) over the acute period. Compared to those who fully recovered, those reporting PASC demonstrated significantly higher maximum levels of SARS-CoV-2 RNA and N-antigen, burden of RNA and infectious viral shedding, and lower Spike-specific IgG levels within 9 days post-illness onset. No significant differences were identified among a panel of host immune markers. Our results suggest early viral dynamics and the associated host immune responses play a role in the pathogenesis of PASC, highlighting the importance of understanding early biological markers in the natural history of PASC.

PURPOSE: To investigate the prevalence, patterns, and predictors of SARS-CoV-2 RNA and culturable virus in tears of a case-ascertained household cohort. DESIGN: Prospective, longitudinal case-ascertained household cohort identified through convenience sampling. METHODS: This analysis was restricted to individuals who were non-hospitalized, symptomatic, and tested positive for SARS-CoV-2 by nasal RT-PCR. Tears and anterior nasal biospecimens were serially collected throughout the acute period. Tears specimens were collected by the study staff using Schirmer test strips, and nasal specimens were self-collected. For both, SARS-CoV-2 RNA was quantified using qRT-PCR, and culturable virus was detected using presence of cytopathic effect (CPE) in tissue culture; positive CPE was confirmed by a qRT-PCR step. A series of cross-sectional unadjusted analyses were performed investigating the relationship between different sociodemographic determinants and biological factors associated with tears RNA positivity. RESULTS: Among the 83 SARS-CoV-2 infected participants, 10 (12%) had at least one RNA-positive tears specimen. Amongst these 10, 5 (50%) had concurrent presence of culturable virus, at a median of 7 days postsymptom onset (IQR: 4-7 days) (absolute range: 4-8 days). CONCLUSIONS: In this longitudinal cohort, we found evidence of culturable virus in the tears of a small proportion of nonhospitalized SARS-CoV-2 infected individuals. Current public health infection precautions do not account for transmission via tears, so these findings may improve our understanding of potential sources of SARS-CoV-2 transmission and contribute to developing future guidelines.

During the 2022 multinational outbreak of monkeypox virus (MPXV) infection, the antiviral drug tecovirimat (TPOXX; SIGA Technologies, Inc., https://www.siga.com) was deployed in the United States on a large scale for the first time. The MPXV F13L gene homologue encodes the target of tecovirimat, and single amino acid changes in F13 are known to cause resistance to tecovirimat. Genomic sequencing identified 11 mutations previously reported to cause resistance, along with 13 novel mutations. Resistant phenotype was determined using a viral cytopathic effect assay. We tested 124 isolates from 68 patients; 96 isolates from 46 patients were found to have a resistant phenotype. Most resistant isolates were associated with severely immunocompromised mpox patients on multiple courses of tecovirimat treatment, whereas most isolates identified by routine surveillance of patients not treated with tecovirimat remained sensitive. The frequency of resistant viruses remains relatively low (<1%) compared with the total number of patients treated with tecovirimat.

During July 7-11, 2023, CDC received reports of two patients in different states with a tuberculosis (TB) diagnosis following spinal surgical procedures that used bone allografts containing live cells from the same deceased donor. An outbreak associated with a similar product manufactured by the same tissue establishment (i.e., manufacturer) occurred in 2021. Because of concern that these cases represented a second outbreak, CDC and the Food and Drug Administration worked with the tissue establishment to determine that this product was obtained from a donor different from the one implicated in the 2021 outbreak and learned that the bone allograft product was distributed to 13 health care facilities in seven states. Notifications to all seven states occurred on July 12. As of December 20, 2023, five of 36 surgical bone allograft recipients received laboratory-confirmed TB disease diagnoses; two patients died of TB. Whole-genome sequencing demonstrated close genetic relatedness between positive Mycobacterium tuberculosis cultures from surgical recipients and unused product. Although the bone product had tested negative by nucleic acid amplification testing before distribution, M. tuberculosis culture of unused product was not performed until after the outbreak was recognized. The public health response prevented up to 53 additional surgical procedures using allografts from that donor; additional measures to protect patients from tissue-transmitted M. tuberculosis are urgently needed.

OBJECTIVE: To develop initial American College of Rheumatology (ACR) guidelines on the use of exercise, rehabilitation, diet, and additional interventions in conjunction with disease-modifying antirheumatic drugs (DMARDs) as part of an integrative management approach for people with rheumatoid arthritis (RA). METHODS: An interprofessional guideline development group constructed clinically relevant Population, Intervention, Comparator, and Outcome (PICO) questions. A literature review team then completed a systematic literature review and applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate the certainty of evidence. An interprofessional Voting Panel (n = 20 participants) that included 3 individuals with RA achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: The Voting Panel achieved consensus on 28 recommendations for the use of integrative interventions in conjunction with DMARDs for the management of RA. Consistent engagement in exercise received a strong recommendation. Of 27 conditional recommendations, 4 pertained to exercise, 13 to rehabilitation, 3 to diet, and 7 to additional integrative interventions. These recommendations are specific to RA management, recognizing that other medical indications and general health benefits may exist for many of these interventions. CONCLUSION: This guideline provides initial ACR recommendations on integrative interventions for the management of RA to accompany DMARD treatments. The broad range of interventions included in these recommendations illustrates the importance of an interprofessional, team-based approach to RA management. The conditional nature of most recommendations requires clinicians to engage persons with RA in shared decision-making when applying these recommendations.

Tecovirimat, also known as TPOXX or ST-246, is a drug available for the treatment of mpox. Tecovirimat targets the conserved orthopoxvirus VP37 protein (also known as F13) required for extracellular virus particle generation (1, 2). Multiple VP37 mutations associated with tecovirimat resistance have been reported within the current global mpox outbreak in immunocompromised individuals with advanced HIV infection (3 – 5). In many of these cases, resistance mutation heterogeneity was observed following tecovirimat exposure, suggesting resistance emerged under selective pressure during treatment. | To monitor circulating monkeypox virus (MPXV) within California, a genomic surveillance network was established whereby clinical and commercial laboratories provided positive specimens for whole-genome sequencing using an amplicon-based protocol and subsequent analysis (6 – 9). Through this surveillance, 11 mpox cases were identified in southern California with the same tecovirimat resistance-associated mutation (Table 1): a three-nucleotide deletion in the vaccinia virus Copenhagen F13L gene homolog (OPG057) resulting in asparagine removed from position 267 in the VP37 protein (VP37:N267del) (5) (https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/fda-mpox-response#therapeutics). VP37:N267del was the only tecovirimat resistance-associated mutation detected in identified specimens and had allele frequencies greater than 89% in all instances, suggesting infections may have occurred with predominantly mutant virus. Phenotypic testing in vitro (3 – 5) confirmed tecovirimat resistance in ten identified specimens with EC50 values ranging from 1.488 to 3.977 µM, corresponding to an 85- to 230-fold change compared to wild-type isolates.

This study aimed to estimate dietary sodium and potassium consumption among Jamaicans and evaluate associations with sociodemographic and clinical characteristics. A cross-sectional study was conducted using data from the Jamaica Health and Lifestyle Survey 2016-2017. Participants were noninstitutionalized Jamaicans aged ≥15 years. Trained staff collected sociodemographic and health data via interviewer-administered questionnaires and spot urine samples. The Pan American Health Organization formula was used to estimate 24-hour urine sodium and potassium excretion. High sodium level was defined as ≥2000 mg/day, and low potassium levels as <3510 mg/day (World Health Organization criteria). Associations between these outcomes and sociodemographic and clinical characteristics were explored using multivariable ANOVA models using log-transformed 24-hour urine sodium and potassium as outcome variables. Analyses included 1009 participants (368 males, 641 females; mean age 48.5 years). The mean sodium excretion was 3582 mg/day (males 3943 mg/day, females 3245 mg/day, P < .001). The mean potassium excretion was 2052 mg/day (males, 2210 mg/day; females, 1904 mg/day; P = .001). The prevalence of high sodium consumption was 66.6% (males 72.8%, females 60.7%, P < .001) and that of low potassium intake was 88.8% (85.1% males, 92.3% females, P < .001). Sodium consumption was inversely associated with older age, higher education, and low glomerular filtration rate but was directly associated with being male, current smoking, and obesity. Overall, males had higher sodium consumption than women, with the effect being larger among hypertensive men. Women with hypertension had lower sodium consumption than nonhypertensive women; however, hypertensive men had higher sodium consumption than nonhypertensive men. Potassium consumption was higher among men, persons with obesity, and those with high total cholesterol but was lower among men with "more than high school" education compared to men with "less than high school" education. We conclude that most Jamaican adults have diets high in sodium and low in potassium. In this study, sodium consumption was directly associated with male sex, obesity, and current smoking but was inversely associated with older age and higher education. High potassium consumption was associated with obesity and high cholesterol levels. These associations should be further explored in longitudinal studies and population-based strategies should be developed to address these cardiovascular risk factors.

BACKGROUND: The influence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA level and presence of infectious virus on symptom occurrence is poorly understood, particularly among nonhospitalized individuals. METHODS: The study included 85 nonhospitalized, symptomatic adults, who were enrolled from September 2020 to November 2021. Data from a longitudinal cohort studied over 28 days was used to analyze the association of individual symptoms with SARS-CoV-2 viral RNA load, or the presence or level of infectious (culturable) virus. Presence of infectious virus and viral RNA load were assessed daily, depending on specimen availability, and amount of infectious virus was assessed on the day of maximum RNA load. Participants were surveyed for the start and end dates of 31 symptoms at enrollment and at days 9, 14, 21, and 28; daily symptom presence was determined analytically. We describe symptoms and investigate their possible association with viral determinants through a series of single or pooled (multiple days across acute period) cross-sectional analyses. RESULTS: There was an association between viral RNA load and the same-day presence of many individual symptoms. Additionally, individuals with infectious virus were more than three times as likely to have a concurrent fever than individuals without infectious virus, and more than two times as likely to have concurrent myalgia, chills, headache, or sore throat. CONCLUSIONS: We found evidence to support the association of viral RNA load and infectious virus on some, but not all symptoms. Fever was most strongly associated with the presence of infectious virus; this may support the potential for symptom-based isolation guidance for COVID-19.

Approximately 6 months before an unprecedented global mpox outbreak was first identified in the United Kingdom, an adult man was diagnosed with mpox in Maryland, USA [1]. At the time of the investigation, the case was only the eighth monkeypox virus (MPXV) infection diagnosed in a non-African country during the preceding 3 years, all of which were associated with recent travel to Nigeria [2]. One of these 8 imported cases occurred in Texas, USA four months earlier; that case exhibited features clinically consistent with those classically reported in Africa (i.e., large and diffuse lesions, high fever and prodromal symptoms, umbilicated lesions in the same stage of development on specific anatomic surfaces) [3]. In contrast, the Maryland case was milder in severity and had signs that, at the time, were considered unusual for mpox. Several aspects of the Maryland case are noteworthy and in retrospect may offer clues to the origins of the 2022 global mpox outbreak, as well as explain how mpox might have spread undetected before emerging as a global outbreak.

Background: During the 2022 multinational outbreak of monkeypox virus (MPXV) clade IIb, the antiviral drug tecovirimat (TPOXX) was deployed in the US on a large scale for the first time ever. The MPXV F13L gene homolog encodes the target of tecovirimat, and single amino acid changes in the F13 protein are known to cause resistance to tecovirimat in orthopoxviruses (OPXV). Method(s): Whole genome metagenomic sequencing and amplicon-based sequencing targeting the F13L gene was used to identify nine mutations previously reported to cause resistance in other OPXV along with ten novel mutations that have been identified from the 2022 mpox outbreak. A cytopathic effect assay, previously established at CDC as part of WHO smallpox research, was adapted to MPXV for tecovirimat phenotype testing of virus isolated from mpox patients. Result(s): As of March 2023, in total, 70 isolates from 40 patients were tested, and 50 of these isolates from 26 patients were found to have a resistant phenotype. Most resistant isolates were associated with severely immunocompromised mpox patients on multiple courses of TPOXX treatment; while isolates with F13 mutations identified by routine surveillance of patients not treated with TPOXX have remained sensitive. Conclusion(s): These data indicate that tecovirimat resistance is developing in immunocompromised patients treated with TPOXX and that for isolates that we have analyzed, the frequency of resistant viruses remain relatively low (< 1%) compared to the total number of patients treated with TPOXX. These findings inform our understanding of when tecovirimat resistance is likely to occur and highlight the need for additional OPXV therapeutics. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.

Objective: To estimate dietary sodium and potassium consumption among Jamaicans and evaluate associations with sociodemographic and clinical characteristics. Method(s): We conducted a cross-sectional analysis of data from the Jamaica Health and Lifestyle Survey 2016-2017. Participants were non-institutionalized Jamaicans, >=15 years. Trained staff collected sociodemographic and health data via interviewer administered questionnaires and collected spot urine samples. The Pan American Health Organization Formulae were used to estimate 24-hour urine sodium and potassium excretion. High sodium was defined as >=2000 mg/day and low potassium as <3510 mg/day (World Health Organization criteria). Associations of these outcomes with sociodemographic and clinical characteristics were explored in sex specific multivariable ANOVA models. Result(s): Analyses included 1009 participants (368 males, 641 females; mean age 48.5 years). Mean sodium excretion was 3582 mg/day (males 3943 mg/day, females 3245 mg/day, p<0.001). Mean potassium excretion was 2052 mg/day (males 2210 mg/day, females 1904 mg/day, p=0.001). The prevalence of high sodium consumption was 66.6% (males 72.8%, female 60.7%, p<0.001) and low potassium intake was 88.8% (85.1% males, 92.3% females, p<0.001). Among males, sodium consumption was inversely associated with older age and prehypertension, but directly associated with current smoking and obesity. Among females, sodium consumption was inversely associated with hypertension, impaired fasting glucose, low GFR and high physical activity, but was directly associated with obesity. Conclusion(s): Most Jamaican adults have diets high in sodium and low in potassium. Sodium consumption was directly associated with obesity in both men and women. Population based strategies are therefore required to address these cardiovascular risk factors. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.

Wastewater-based epidemiology (WBE) emerged during the COVID-19 pandemic as a scalable and broadly applicable method for community-level monitoring of infectious disease burden, though the lack of high-quality, longitudinal fecal shedding data of SARS-CoV-2 and other viruses limits the interpretation and applicability of wastewater measurements. In this study, we present longitudinal, quantitative fecal shedding data for SARS-CoV-2 RNA, as well as the commonly used fecal indicators Pepper Mild Mottle Virus (PMMoV) RNA and crAss-like phage (crAssphage) DNA. The shedding trajectories from 48 SARS-CoV-2 infected individuals suggest a highly individualized, dynamic course of SARS-CoV-2 RNA fecal shedding, with individual measurements varying from below limit of detection to 2.79x106 gene copies/mg - dry mass of stool (gc/mg-dw). Of individuals that contributed at least 3 samples covering a range of at least 15 of the first 30 days after initial acute symptom onset, 77.4% had at least one positive SARS-CoV-2 RNA stool sample measurement. We detected PMMoV RNA in at least one sample from all individuals and in 96% (352/367) of samples overall; and measured crAssphage DNA above detection limits in 80% (38/48) of individuals and 48% (179/371) of samples. Median shedding values for PMMoV and crAssphage nucleic acids were 1x105 gc/mg-dw and 1.86x103 gc/mgdw, respectively. These results can be used to inform and build mechanistic models to significantly broaden the potential of WBE modeling and to provide more accurate insight into SARS-CoV-2 prevalence estimates. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.

Monkeypox is a viral zoonotic disease endemic in Central and West Africa. In May 2022, dozens of non-endemic countries reported hundreds of monkeypox cases, most with no epidemiological link to Africa. We identified two lineages of Monkeypox virus (MPXV) among nine 2021 and 2022 U.S. monkeypox cases. A 2021 case was highly similar to the 2022 MPXV outbreak variant, suggesting a common ancestor. Analysis of mutations among these two lineages revealed an extreme preference for GA-to-AA mutations indicative of APOBEC3 cytosine deaminase activity that was shared among West African MPXV since 2017 but absent from Congo Basin lineages. Poxviruses are not thought to be subject to APOBEC3 editing; however, these findings suggest APOBEC3 activity has been recurrent and dominant in recent West African MPXV evolution. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.

Genomic surveillance of monkeypox virus (MPXV) during the 2022 outbreak has been mainly focused on single nucleotide polymorphism (SNP) changes. DNA viruses, including MPXV, have a lower SNP mutation rate than RNA viruses due to higher fidelity replication machinery. We identified a large genomic rearrangement in a MPXV sequence from a 2022 case in the state of Minnesota (MN), USA, from an abnormal, uneven MPXV read mapping coverage profile in whole-genome sequencing (WGS) data. We further screened WGS data of 206 U.S. MPXV samples and found seven (3.4 percent) sequenced genomes contained similar abnormal read coverage profiles that suggested putative large deletions or genomic rearrangements. Here, we present three MPXV genomes containing deletions ranging from 2.3 to 15 kb and four genomes containing more complex rearrangements. Five genomic changes were each only seen in one sample, but two sequences from linked cases shared an identical 2.3 kb deletion in the 3' terminal region. All samples were positive using VAC1 and Clade II (formerly West African)-specific MPXV diagnostic tests; however, large deletions and genomic rearrangements like the ones reported here have the potential to result in viruses in which the target of a PCR diagnostic test is deleted. The emergence of genomic rearrangements during the outbreak may have public health implications and highlight the importance of continued genomic surveillance. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.

The impact of vaccination on SARS-CoV-2 infectiousness is not well understood. We compared longitudinal viral shedding dynamics in unvaccinated and fully vaccinated adults. SARS-CoV-2-infected adults were enrolled within 5 days of symptom onset and nasal specimens were self-collected daily for two weeks and intermittently for an additional two weeks. SARS-CoV-2 RNA load and infectious virus were analyzed relative to symptom onset stratified by vaccination status. We tested 1080 nasal specimens from 52 unvaccinated adults enrolled in the pre-Delta period and 32 fully vaccinated adults with predominantly Delta infections. While we observed no differences by vaccination status in maximum RNA levels, maximum infectious titers and the median duration of viral RNA shedding, the rate of decay from the maximum RNA load was faster among vaccinated; maximum infectious titers and maximum RNA levels were highly correlated. Furthermore, amongst participants with infectious virus, median duration of infectious virus detection was reduced from 7.5 days (IQR: 6.0-9.0) in unvaccinated participants to 6 days (IQR: 5.0-8.0) in those vaccinated (P=0.02). Accordingly, the odds of shedding infectious virus from days 6 to 12 post-onset were lower among vaccinated participants than unvaccinated participants (OR 0.42 95% CI 0.19-0.89). These results indicate that vaccination had reduced the probability of shedding infectious virus after 5 days from symptom onset. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.

Tecovirimat (also known as TPOXX or ST-246) is a drug available for the treatment of mpox through the Centers for Disease Control and Prevention’s Expanded Access Investigational New Drug “compassionate use” protocol (https://www.cdc.gov/poxvirus/monkeypox/clinicians/Tecovirimat.html). In Los Angeles County, a fatal case of mpox with tecovirimat resistance was previously reported (1). Epidemiologic surveillance in Los Angeles County has since identified additional cases of severe mpox that did not improve after multiple rounds of tecovirimat treatment, including one involving a person who succumbed to infection (Table 1). Consistent with reports describing severe manifestations of mpox within the current global outbreak (1, 2), the identified cases involved host immunodeficiency due to advanced HIV infection.

Updated (bivalent) COVID-19 vaccines were first recommended by CDC on September 1, 2022.* An analysis of case and death rates by vaccination status shortly after authorization of bivalent COVID-19 vaccines showed that receipt of a bivalent booster dose provided additional protection against SARS-CoV-2 infection and associated death (1). In this follow-up report on the durability of bivalent booster protection against death among adults aged ≥65 years, mortality rate ratios (RRs) were estimated among unvaccinated persons and those who received a bivalent booster dose by time since vaccination during three periods of Omicron lineage predominance (BA.5 [September 18–November 5, 2022], BQ.1/BQ.1.1 [November 6, 2022–January 21, 2023], and XBB.1.5 [January 22–April 1, 2023]).† | | During September 18, 2022–April 1, 2023, weekly counts of COVID-19–associated deaths§ among unvaccinated persons and those who received a bivalent booster dose¶ were reported from 20 U.S. jurisdictions** that routinely link case surveillance data to immunization registries and vital registration databases (1). Vaccinated persons who did not receive a bivalent COVID-19 booster dose were excluded. Rate denominators were calculated from vaccine administration data and 2019 U.S. intercensal population estimates,†† with numbers of unvaccinated persons estimated by subtracting numbers of vaccinated persons from the 2019 intercensal population estimates, as previously described§§ (1). Average weekly mortality rates were estimated based on date of specimen collection¶¶ during each variant period by vaccination status and time since bivalent booster dose receipt. RRs were calculated by dividing rates among unvaccinated persons by rates among bivalent booster dose recipients; after detrending the underlying linear changes in weekly rates, 95% CIs were estimated from the remaining variation in rates observed*** (1). SAS (version 9.4; SAS Institute) and R (version 4.1.2; R Foundation) software were used to conduct all analyses. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.†††

Wastewater-based epidemiology (WBE) emerged during the coronavirus disease 2019 (COVID-19) pandemic as a scalable and broadly applicable method for community-level monitoring of infectious disease burden. The lack of high-resolution fecal shedding data for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) limits our ability to link WBE measurements to disease burden. In this study, we present longitudinal, quantitative fecal shedding data for SARS-CoV-2 RNA, as well as for the commonly used fecal indicators pepper mild mottle virus (PMMoV) RNA and crAss-like phage (crAssphage) DNA. The shedding trajectories from 48 SARS-CoV-2-infected individuals suggest a highly individualized, dynamic course of SARS-CoV-2 RNA fecal shedding. Of the individuals that provided at least three stool samples spanning more than 14 days, 77% had one or more samples that tested positive for SARS-CoV-2 RNA. We detected PMMoV RNA in at least one sample from all individuals and in 96% (352/367) of samples overall. CrAssphage DNA was detected in at least one sample from 80% (38/48) of individuals and was detected in 48% (179/371) of all samples. The geometric mean concentrations of PMMoV and crAssphage in stool across all individuals were 8.7 × 10(4) and 1.4 × 10(4) gene copies/milligram-dry weight, respectively, and crAssphage shedding was more consistent for individuals than PMMoV shedding. These results provide us with a missing link needed to connect laboratory WBE results with mechanistic models, and this will aid in more accurate estimates of COVID-19 burden in sewersheds. Additionally, the PMMoV and crAssphage data are critical for evaluating their utility as fecal strength normalizing measures and for source-tracking applications. IMPORTANCE This research represents a critical step in the advancement of wastewater monitoring for public health. To date, mechanistic materials balance modeling of wastewater-based epidemiology has relied on SARS-CoV-2 fecal shedding estimates from small-scale clinical reports or meta-analyses of research using a wide range of analytical methodologies. Additionally, previous SARS-CoV-2 fecal shedding data have not contained sufficient methodological information for building accurate materials balance models. Like SARS-CoV-2, fecal shedding of PMMoV and crAssphage has been understudied to date. The data presented here provide externally valid and longitudinal fecal shedding data for SARS-CoV-2, PMMoV, and crAssphage which can be directly applied to WBE models and ultimately increase the utility of WBE.

OBJECTIVE: To develop initial American College of Rheumatology (ACR) guidelines on the use of exercise, rehabilitation, diet, and additional interventions in conjunction with disease-modifying antirheumatic drugs (DMARDs) as part of an integrative management approach for people with rheumatoid arthritis (RA). METHODS: An interprofessional guideline development group constructed clinically relevant Population, Intervention, Comparator, and Outcome (PICO) questions. A literature review team then completed a systematic literature review and applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate the certainty of evidence. An interprofessional Voting Panel (n = 20 participants) that included 3 individuals with RA achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: The Voting Panel achieved consensus on 28 recommendations for the use of integrative interventions in conjunction with DMARDs for the management of RA. Consistent engagement in exercise received a strong recommendation. Of 27 conditional recommendations, 4 pertained to exercise, 13 to rehabilitation, 3 to diet, and 7 to additional integrative interventions. These recommendations are specific to RA management, recognizing that other medical indications and general health benefits may exist for many of these interventions. CONCLUSION: This guideline provides initial ACR recommendations on integrative interventions for the management of RA to accompany DMARD treatments. The broad range of interventions included in these recommendations illustrates the importance of an interprofessional, team-based approach to RA management. The conditional nature of most recommendations requires clinicians to engage persons with RA in shared decision-making when applying these recommendations.

Since May 2022, when the multinational mpox (formerly known as monkeypox) clade IIb virus outbreak was first reported, more than 30,000 cases have been identified in the United States.1 In one study involving more than 1900 patients with mpox, more than 35% of the patients also had human immunodeficiency virus (HIV) infection.2 | | We report a death due to mpox in a patient in the United States. A 33-year-old man with HIV infection (CD4+ T-cell count, <35 per cubic millimeter) and recently treated syphilis became infected with mpox virus (MPXV) (clade IIb). He received two courses of oral tecovirimat (from Aug. 6 through Aug. 20, 2022, and from Aug. 21 through Sept. 4, 2022) and died on hospital day 27.

From two SARS-CoV-2 household transmission studies (enrolling April 2020 - January 2022) with rapid enrollment and specimen collection for 14 days, 61% (43/70) of primary cases had culturable-virus detected ≥6 days post-onset. Risk of secondary infection among household contacts tended to be greater when primary cases had culturable-virus detected after onset. Regardless of duration of culturable-virus, most secondary infections [70% (28/40)] had serial intervals <6 days, suggesting early transmission. These data examine viral culture as a proxy for infectiousness, reaffirm the need for rapid control measures after infection and highlight the potential for prolonged infectiousness (≥6 days) in many individuals.

Monkeypox is a viral zoonotic disease endemic in Central and West Africa. In May 2022, dozens of non-endemic countries reported hundreds of monkeypox cases, most with no epidemiological link to Africa. We identified two lineages of monkeypox virus (MPXV) among two 2021 and seven 2022 U.S. monkeypox cases: the major 2022 outbreak variant, B.1, and a minor contemporaneously sampled variant called A.2. Analyses of mutations among these two variants revealed an extreme preference for GA-to-AA mutations indicative of human APOBEC3 cytosine deaminase activity among Clade IIb MPXV (previously West African, Nigeria) sampled since 2017. Such mutations were not enriched within other MPXV clades. These findings suggest that APOBEC3 editing may be a recurrent and a dominant driver of MPXV evolution within the current outbreak.

OBJECTIVE: To determine the proportion of hospitals that implemented 6 leading practices in their antimicrobial stewardship programs (ASPs). Design: Cross-sectional observational survey. SETTING: Acute-care hospitals. PARTICIPANTS: ASP leaders. METHODS: Advance letters and electronic questionnaires were initiated February 2020. Primary outcomes were percentage of hospitals that (1) implemented facility-specific treatment guidelines (FSTG); (2) performed interactive prospective audit and feedback (PAF) either face-to-face or by telephone; (3) optimized diagnostic testing; (4) measured antibiotic utilization; (5) measured C. difficile infection (CDI); and (6) measured adherence to FSTGs. RESULTS: Of 948 hospitals invited, 288 (30.4%) completed the questionnaire. Among them, 82 (28.5%) had <99 beds, 162 (56.3%) had 100-399 beds, and 44 (15.2%) had ≥400+ beds. Also, 230 (79.9%) were healthcare system members. Moreover, 161 hospitals (54.8%) reported implementing FSTGs; 214 (72.4%) performed interactive PAF; 105 (34.9%) implemented procedures to optimize diagnostic testing; 235 (79.8%) measured antibiotic utilization; 258 (88.2%) measured CDI; and 110 (37.1%) measured FSTG adherence. Small hospitals performed less interactive PAF (61.0%; P = .0018). Small and nonsystem hospitals were less likely to optimize diagnostic testing: 25.2% (P = .030) and 21.0% (P = .0077), respectively. Small hospitals were less likely to measure antibiotic utilization (67.8%; P = .0010) and CDI (80.3%; P = .0038). Nonsystem hospitals were less likely to implement FSTGs (34.3%; P < .001). CONCLUSIONS: Significant variation exists in the adoption of ASP leading practices. A minority of hospitals have taken action to optimize diagnostic testing and measure adherence to FSTGs. Additional efforts are needed to expand adoption of leading practices across all acute-care hospitals with the greatest need in smaller hospitals.

Since May 2022, approximately 20,000 cases of monkeypox have been identified in the United States, part of a global outbreak occurring in approximately 90 countries and currently affecting primarily gay, bisexual, and other men who have sex with men (MSM) (1). Monkeypox virus (MPXV) spreads from person to person through close, prolonged contact; a small number of cases have occurred in populations who are not MSM (e.g., women and children), and testing is recommended for persons who meet the suspected case definition* (1). CDC previously developed five real-time polymerase chain reaction (PCR) assays for detection of orthopoxviruses from lesion specimens (2,3). CDC was granted 510(k) clearance for the nonvariola-orthopoxvirus (NVO)-specific PCR assay by the Food and Drug Administration. This assay was implemented within the Laboratory Response Network (LRN) in the early 2000s and became critical for early detection of MPXV and implementation of public health action in previous travel-associated cases as well as during the current outbreak (4-7). PCR assays (NVO and other Orthopoxvirus laboratory developed tests [LDT]) represent the primary tool for monkeypox diagnosis. These tests are highly sensitive, and cross-contamination from other MPXV specimens being processed, tested, or both alongside negative specimens can occasionally lead to false-positive results. This report describes three patients who had atypical rashes and no epidemiologic link to a monkeypox case or known risk factors; these persons received diagnoses of monkeypox based on late cycle threshold (Ct) values ≥34, which were false-positive test results. The initial diagnoses were followed by administration of antiviral treatment (i.e., tecovirimat) and JYNNEOS vaccine postexposure prophylaxis (PEP) to patients' close contacts. After receiving subsequent testing, none of the three patients was confirmed to have monkeypox. Knowledge gained from these and other cases resulted in changes to CDC guidance. When testing for monkeypox in specimens from patients without an epidemiologic link or risk factors or who do not meet clinical criteria (or where these are unknown), laboratory scientists should reextract and retest specimens with late Ct values (based on this report, Ct ≥34 is recommended) (8). CDC can be consulted for complex cases including those that appear atypical or questionable cases and can perform additional viral species- and clade-specific PCR testing and antiorthopoxvirus serologic testing.

The impact of vaccination on SARS-CoV-2 infectiousness is not well understood. We compared longitudinal viral shedding dynamics in unvaccinated and fully vaccinated adults. SARS-CoV-2-infected adults were enrolled within 5 days of symptom onset and nasal specimens were self-collected daily for two weeks and intermittently for an additional two weeks. SARS-CoV-2 RNA load and infectious virus were analyzed relative to symptom onset stratified by vaccination status. We tested 1080 nasal specimens from 52 unvaccinated adults enrolled in the pre-Delta period and 32 fully vaccinated adults with predominantly Delta infections. While we observed no differences by vaccination status in maximum RNA levels, maximum infectious titers and the median duration of viral RNA shedding, the rate of decay from the maximum RNA load was faster among vaccinated; maximum infectious titers and maximum RNA levels were highly correlated. Furthermore, amongst participants with infectious virus, median duration of infectious virus detection was reduced from 7.5 days (IQR: 6.0-9.0) in unvaccinated participants to 6 days (IQR: 5.0-8.0) in those vaccinated (P = 0.02). Accordingly, the odds of shedding infectious virus from days 6 to 12 post-onset were lower among vaccinated participants than unvaccinated participants (OR 0.42 95% CI 0.19-0.89). These results indicate that vaccination had reduced the probability of shedding infectious virus after 5 days from symptom onset.

BACKGROUND: Measuring clinically relevant opioid-related problems in health care systems is challenging due to the lack of standard definitions and coding practices. Well-defined, opioid-related health problems (ORHPs) would improve prevalence estimates and evaluation of clinical interventions, crisis response, and prevention activities. We sought to estimate prevalence of opioid use disorder (OUD), opioid misuse, and opioid poisoning among inpatients at a large, safety net, health care institution. METHODS: Our study included events documented in the electronic health records (EHRs) among hospitalized patients at Denver Health Medical Center during January 1, 2017 to December 31, 2018. Multiple EHR markers (ie, opioid-related diagnostic codes, clinical assessment, laboratory results, and free-text documentation) were used to develop diagnosis-based and extended definitions for OUD, opioid misuse, and opioid poisoning. We used these definitions to estimate number of hospitalized patients with these conditions. RESULTS: During a 2-year study period, 715 unique patients were identified solely using opioid-related diagnostic codes; OUD codes accounted for the largest proportion (499/715, 69.8%). Extended definitions identified an additional 973 unique patients (~136% increase), which includes 155/973 (15.9%) who were identified by a clinical assessment marker, 1/973 (0.1%) by a laboratory test marker, and 817/973 (84.0%) by a clinical documentation marker. CONCLUSIONS: Solely using diagnostic codes to estimate prevalence of clinically relevant ORHPs missed most patients with ORHPs. More inclusive estimates were generated using additional EHR markers. Improved methods to estimate ORHPs among a health care system's patients would more fully estimate organizational and economic burden to more efficiently allocate resources and ensure capacity to provide clinical services.

As part of public health preparedness for infectious disease threats, CDC collaborates with other U.S. public health officials to ensure that the Laboratory Response Network (LRN) has diagnostic tools to detect Orthopoxviruses, the genus that includes Variola virus, the causative agent of smallpox. LRN is a network of state and local public health, federal, U.S. Department of Defense (DOD), veterinary, food, and environmental testing laboratories. CDC developed, and the Food and Drug Administration (FDA) granted 510(k) clearance* for the Non-variola Orthopoxvirus Real-time PCR Primer and Probe Set (non-variola Orthopoxvirus [NVO] assay), a polymerase chain reaction (PCR) diagnostic test to detect NVO. On May 17, 2022, CDC was contacted by the Massachusetts Department of Public Health (DPH) regarding a suspected case of monkeypox, a disease caused by the Orthopoxvirus Monkeypox virus. Specimens were collected and tested by the Massachusetts DPH public health laboratory with LRN testing capability using the NVO assay. Nationwide, 68 LRN laboratories had capacity to test approximately 8,000 NVO tests per week during June. During May 17-June 30, LRN laboratories tested 2,009 specimens from suspected monkeypox cases. Among those, 730 (36.3%) specimens from 395 patients were positive for NVO. NVO-positive specimens from 159 persons were confirmed by CDC to be monkeypox; final characterization is pending for 236. Prompt identification of persons with infection allowed rapid response to the outbreak, including isolation and treatment of patients, administration of vaccines, and other public health action. To further facilitate access to testing and increase convenience for providers and patients by using existing provider-laboratory relationships, CDC and LRN are supporting five large commercial laboratories with a national footprint (Aegis Science, LabCorp, Mayo Clinic Laboratories, Quest Diagnostics, and Sonic Healthcare) to establish NVO testing capacity of 10,000 specimens per week per laboratory. On July 6, 2022, the first commercial laboratory began accepting specimens for NVO testing based on clinician orders.