The CDC Domestic Mpox Response - United States, 2022-2023.

Monkeypox (mpox) is a serious viral zoonosis endemic in west and central Africa. An unprecedented global outbreak was first detected in May 2022. CDC activated its emergency outbreak response on May 23, 2022, and the outbreak was declared a Public Health Emergency of International Concern on July 23, 2022, by the World Health Organization (WHO),* and a U.S. Public Health Emergency on August 4, 2022, by the U.S. Department of Health and Human Services.† A U.S. government response was initiated, and CDC coordinated activities with the White House, the U.S. Department of Health and Human Services, and many other federal, state, and local partners. CDC quickly adapted surveillance systems, diagnostic tests, vaccines, therapeutics, grants, and communication systems originally developed for U.S. smallpox preparedness and other infectious diseases to fit the unique needs of the outbreak. In 1 year, more than 30,000 U.S. mpox cases were reported, more than 140,000 specimens were tested, >1.2 million doses of vaccine were administered, and more than 6,900 patients were treated with tecovirimat, an antiviral medication with activity against orthopoxviruses such as Variola virus and Monkeypox virus. Non-Hispanic Black (Black) and Hispanic or Latino (Hispanic) persons represented 33% and 31% of mpox cases, respectively; 87% of 42 fatal cases occurred in Black persons. Sexual contact among gay, bisexual, and other men who have sex with men (MSM) was rapidly identified as the primary risk for infection, resulting in profound changes in our scientific understanding of mpox clinical presentation, pathogenesis, and transmission dynamics. This report provides an overview of the first year of the response to the U.S. mpox outbreak by CDC, reviews lessons learned to improve response and future readiness, and previews continued mpox response and prevention activities as local viral transmission continues in multiple U.S. jurisdictions (Figure).

Vital Signs: Trends in Human Rabies Deaths and Exposures - United States, 1938-2018.

INTRODUCTION: Each year, rabies causes approximately 59,000 deaths worldwide, including approximately two deaths in the United States. Before 1960, dogs were a common reservoir of rabies in the United States; however, increasingly, species of wildlife (e.g., bats, raccoons) are the main reservoirs. This report characterizes human rabies deaths, summarizes trends in rabies mortality, and highlights current rabies risks in the United States. METHODS: Rabies trends in the United States during 1938-2018 were analyzed using national rabies surveillance data. Data from the Healthcare Cost and Utilization Project for 2006-2014 were used to estimate the number of postexposure prophylaxis (PEP) visits per 100,000 persons during 2017-2018. The Centers for Medicare & Medicaid Services' average sales price data were used to estimate PEP costs. RESULTS: From 1960 to 2018, a total of 125 human rabies cases were reported in the United States; 36 (28%) were attributed to dog bites during international travel. Among the 89 infections acquired in the United States, 62 (70%) were attributed to bats. In 2018, approximately 55,000 persons sought PEP after contact with a potentially rabid animal. CONCLUSIONS AND COMMENTS: In the United States, wildlife rabies, especially in bats, continues to pose a risk to humans. Travelers also might be exposed to canine rabies in countries where the disease is still present; increased awareness of rabies while traveling abroad is needed. Vaccinating pets, avoiding contact with wildlife, and seeking medical care if one is bitten or scratched by an animal are the most effective ways to prevent rabies. Understanding the need for timely administration of PEP to prevent death is critical.

Frequent infection of neurons by SV40 virus in SIV-infected macaque monkeys with progressive multifocal leukoencephalopathy and meningoencephalitis.

Simian virus 40 (SV40), family Polyomaviridae, in immunocompromised macaques can cause fatal demyelinating central nervous system disease analogous to progressive multifocal leukoencephalopathy caused by John Cunningham (JC) virus in immunocompromised humans. Recently, we have demonstrated that JC virus can infect cerebellar granule cell neurons and cortical pyramidal neurons in immunosuppressed people. To examine whether SV40 neuronal infection occurs spontaneously in immunosuppressed macaques, we analyzed archival brain specimens from 20 simian immunodeficiency virus-infected rhesus with AIDS and 1 cynomolgus post-transplant selected with SV40 brain infection from archival records from 1991 to 2012. In addition to white matter SV40 distribution in classic demyelinating progressive multifocal leukoencephalopathy, some of the 21 monkeys exhibited meningeal, subpial neocortical, and periventricular virus. This distribution pattern corresponded to broader viral tropism with neuronal infection in 14 (66.7%) of 21 cases. In all 14 cases, identified neurons were positive for early SV40 transcript large T antigen, but only 4 of the 14 cases exhibited late viral transcript viral protein 1-positive neurons. SV40-infected neurons were detected in frontal, parietal, occipital, and temporal cortices, hippocampus, thalamus, and brain stem. These observations confirm that spontaneous SV40 neuronal infection occurs in immunosuppressed macaques, which parallels JC virus-neuronal infection in immunosuppressed patients. Neuronal infection may be an important aspect of both SV40 and JC virus neuropathogenesis in their respective hosts.

The price of incivility.

We've all heard of (or experienced) the "boss from hell." But that's just one form that incivility in the workplace can take. Rudeness on the job is surprisingly common, and it's on the rise. Whether it involves overt bullying or subtle acts of thoughtlessness, incivility takes a toll. It erodes productivity, chips away at morale, leads employees to quit, and damages customer relationships. Dealing with its aftermath can soak up weeks of managerial attention and time. Over the past 14 years the authors have conducted interviews with and collected data from more than 14,000 people throughout the United States and Canada in order to track the prevalence, types, causes, costs, and cures of incivility at work. They suggest several steps leaders can take to counter rudeness. Managers should start with themselves-monitoring their own behavior, asking for feedback on it, and making sure that their actions are a model for others. When it comes to managing the organization, leaders should hire with civility in mind, teach it on the job, create group norms, reward good behavior, and penalize bad behavior. Lest consistent civility seem an extravagance, the authors caution that just one habitually offensive employee critically positioned in an organization can cost millions in Lost employees, lost customers, and lost productivity.

Alternative activation of macrophages in rhesus macaques (Macaca mulatta) with endometriosis.

Endometriosis is one of the most frequently encountered gynecologic diseases and a common cause of chronic pelvic pain and infertility. The pathophysiology of this syndrome can best be described as the presence of ectopic endometrium and a pelvic inflammatory process with associated immune dysfunction and alteration in the peritoneal environment. Macrophages play an important role in the progression and propagation of endometriosis. Alternative macrophage activation occurs in rodents and women with endometriosis but had not been examined previously in nonhuman primates. This case-control study aimed to characterize macrophage polarization in the ectopic and eutopic endometrial tissue of nonhuman primates with and without endometriosis. In addition, circulating cytokines in endometriosis cases and normal controls were investigated in an effort to identify serum factors that contribute to or result from macrophage polarization. Endometriosis lesions demonstrated increased infiltration by macrophages polarized toward the M2 phenotype when compared with healthy control endometrium. No serum cytokine trends consistent with alternative macrophage activation were identified. However, serum transforming growth factor α was elevated in macaques with endometriosis compared with healthy controls. Findings indicated that the activation state of macrophages in endometriosis tissue in nonhuman primates is weighted toward the M2 phenotype. This important finding enables rhesus macaques to serve as an animal model to investigate the contribution of macrophage polarization to the pathophysiology of endometriosis.

Role of a point-of-care protease activity diagnostic test in Canadian clinical practice: a Canadian expert consensus ©.

Nonhealing wounds (stalled, healable) challenge affected individuals, wound clinicians, and society. Nonhealing may result despite local factors being corrected. The interplay between tissue degradation, increased inflammatory response, and abundant protease activity is a challenging quandary. A modified Delphi process was utilized to investigate a protease activity test and practice implications.

Non-human primate model of Kaposi's sarcoma-associated herpesvirus infection.

Since Kaposi's sarcoma-associated herpesvirus (KSHV or human herpesvirus 8) was first identified in Kaposi's sarcoma (KS) lesions of HIV-infected individuals with AIDS, the basic biological understanding of KSHV has progressed remarkably. However, the absence of a proper animal model for KSHV continues to impede direct in vivo studies of viral replication, persistence, and pathogenesis. In response to this need for an animal model of KSHV infection, we have explored whether common marmosets can be experimentally infected with human KSHV. Here, we report the successful zoonotic transmission of KSHV into common marmosets (Callithrix jacchus, Cj), a New World primate. Marmosets infected with recombinant KSHV rapidly seroconverted and maintained a vigorous anti-KSHV antibody response. KSHV DNA and latent nuclear antigen (LANA) were readily detected in the peripheral blood mononuclear cells (PBMCs) and various tissues of infected marmosets. Remarkably, one orally infected marmoset developed a KS-like skin lesion with the characteristic infiltration of leukocytes by spindle cells positive for KSHV DNA and proteins. These results demonstrate that human KSHV infects common marmosets, establishes an efficient persistent infection, and occasionally leads to a KS-like skin lesion. This is the first animal model to significantly elaborate the important aspects of KSHV infection in humans and will aid in the future design of vaccines against KSHV and anti-viral therapies targeting KSHV coinfected tumor cells.

Interleukin-18 predicts atherosclerosis progression in SIV-infected and uninfected rhesus monkeys (Macaca mulatta) on a high-fat/high-cholesterol diet.

Interleukin (IL)-18 levels have been identified as important predictors of cardiovascular mortality and are often elevated in human immunodeficiency virus (HIV)-infected individuals. To investigate a possible function for IL-18 in atherogenesis in the context of early HIV infection, we used the simian immunodeficiency model of HIV infection. Acutely simian immunodeficiency virus-infected and uninfected rhesus monkeys (Macaca mulatta) on an atherogenic diet were evaluated prospectively for atherosclerotic lesion development relative to a panel of plasma markers including IL-18, IL-8, IL-1beta, IL-6, C-reactive protein, soluble vascular cell adhesion molecule-1, soluble E-selectin, and soluble intercellular adhesion molecule-1. Although no significant differences in lesion development were identified between groups after 35 days of infection, levels of plasma IL-18 measured 1 month before virus inoculation correlated significantly with atherosclerotic plaque cross-sectional area at the carotid bifurcation (P<0.001, R=0.946), common iliac bifurcation (P<0.01, R=0.789), and cranial abdominal aorta (P<0.01, R=0.747), as well as with extent of CD3+ and CD68+ cellular infiltration in vascular lesions (both P<0.001, R>or=0.835) in both groups. Atherosclerotic plaque area at the carotid and common iliac bifurcations also showed a weaker inverse correlation with baseline IL-8 levels, as did CD68+ signal area. Results implicate a strong role for IL-18 in early atherosclerosis progression and raise the possibility that the chronically elevated IL-18 levels seen in later stages of HIV infection may contribute significantly to accelerated atherogenesis in this population.

Antigenic stimulation in the simian model of HIV infection yields dilated cardiomyopathy through effects of TNFalpha.

OBJECTIVE: To investigate a role for endogenous myocardial cytokine production in the development of HIV-associated cardiomyopathy. DESIGN: Cardiomyopathy is a late-stage sequela of HIV infection. Although pathogenesis of this condition in HIV infection is poorly defined, inflammatory cytokines are recognized for their detrimental effects on myocardial structure and function. HIV infection is characterized by chronic immune activation and inflammatory cytokine dysregulation. As the myocardium itself is a rich potential source of inflammatory cytokines, HIV-mediated cytokine dysregulation may be an important contributor to development of HIV cardiomyopathy. An antigenic stimulation protocol conducted in the simian immunodeficiency virus (SIV) model of HIV infection was used to study the effects of endogenous cytokine production on myocardial structure and function. METHODS: Twenty-six rhesus monkeys were assigned to treatment groups for a 35-day study. Animals were SIV-infected; SIV-infected and treated with killed Mycobacterium avium complex bacteria (MAC); SIV-infected, MAC-treated, and given the TNFalpha antagonist etanercept; or uninfected and MAC-treated. All animals were subjected to weekly echocardiographic studies. Hearts were collected for further evaluation at euthanasia. RESULTS: SIV-infected, MAC-treated animals developed significant systolic dysfunction [left ventricular ejection fraction (LVEF) decline of 19 +/- 2%] and ventricular chamber dilatation [left ventricular end-diastolic diameter (LVEDD) increase of 26 +/- 6%] not seen in other groups. Concurrent treatment with etanercept prevented development of these changes, implicating a causative role of myocardial TNFalpha. CONCLUSIONS: SIV-infected animals develop exaggerated myocardial pathology on stimulation with the ubiquitous environmental agent MAC. These responses are TNFalpha-dependent and may play a significant role in the development of cardiomyopathy in HIV infection.

Adult attachment as a risk factor for intimate partner violence: the "mispairing" of partners' attachment styles.

This study examined the relationship between intimate partner violence and adult attachment in a sample of 70 couples. The attachment style of each partner and the interaction of the partners' attachment styles were examined as predictors of intimate partner violence. Additional analyses were conducted to examine violence reciprocity and to explore differences in the relationship between attachment and violence using continuous and dichotomous violence measures. Results of hierarchical regression analyses indicated the "mispairing" of an avoidant male partner with an anxious female partner was associated with both male and female violence. When controlling for partner violence, the relationship between attachment and violence was significant for males only. In addition, analyses using a dichotomized violence variable produced different results from analyses using a continuous violence measure. Clinical implications include focusing on the discrepancy between partners' needs for intimacy and distance within the couple as a strategy for treating intimate partner violence.

Phenotypic variation in myocardial macrophage populations suggests a role for macrophage activation in SIV-associated cardiac disease.

Cardiac abnormalities are common in HIV-infected individuals, and have been especially well documented as contributors to mortality in HIV-infected children. Underlying pathogenetic mechanisms responsible for myocardial disease in HIV-infection remain imperfectly understood. SIV-infected rhesus monkeys develop a spectrum of cardiac lesions similar to those seen in HIV-infected people, providing an important model for pathogenesis studies. Retrospective analysis of cardiac tissue collected at necropsy from SIV-infected rhesus monkeys was performed to evaluate myocardial macrophage and dendritic cell populations as a function of previously quantitated lymphocytic inflammatory infiltrates and cardiomyocyte degeneration or necrosis. Variations in the size and phenotype of macrophage and dendritic cell populations were examined as possible contributors to the pathogenesis of SIV-associated inflammatory lesions. Macrophages labeling immunohistochemically for CD163 differed substantially from macrophages labeling for HAM56 in overall number, distribution across groups, involvement in inflammatory clusters, correlation with the DC-SIGN(+) subpopulation of macrophages, and correlation with numbers of SIV-infected cells. CD163(+) macrophages occurred in significantly higher numbers in uninflamed hearts from SIV-infected animals than in hearts from SIV-infected animals with myocarditis or uninfected controls (p < 0.01). Numbers of CD163(+) cells correlated positively with numbers of SIV-infected cells (p < 0.05) suggesting that the CD163(+) population was associated with decreased inflammatory infiltration and reduced control of virus within the heart. As CD163 has been associated with nonclassical macrophage activation and an antiinflammatory phenotype, these results suggest that a balance between classical and nonclassical activation may affect levels of inflammatory infiltration and of myocardial virus burden.

SIV-associated myocarditis: viral and cellular correlates of inflammation severity.

Myocarditis is a common finding in HIV-infected people. Cardiac inflammatory lesions and functional abnormalities similar to those documented in HIV infection are frequently seen in SIV infection of rhesus monkeys, suggesting a shared disease mechanism. A retrospective analysis of cardiac tissue collected at necropsy was performed to assess correlates of myocardial inflammation in SIV-infected rhesus monkeys. Intramyocardial SIV-infected cells were identified in 7 of 21 hearts from SIV-infected animals, with viral protein consistently colocalizing with the macrophage marker HAM 56. Productively infected cells occurred in low numbers, and did not correlate with the presence or quantity of inflammation or necrosis. Intramyocardial CMV was identified in 6 of 21 hearts from SIV+ animals, but also did not correlate with the presence or quantity of inflammation or necrosis. In contrast, T cell infiltration correlated inversely with DC-SIGN+ cell numbers, which occurred in significantly higher numbers in SIV+ animals with histologically normal myocardium than in SIV+ animals with active or borderline myocarditis or in uninfected controls (p < 0.001), suggesting an important immunoregulatory role for this population within the myocardium.

Purification of Enterocytozoon bieneusi from stools and production of specific antibodies.

Enterocytozoon bieneusi is clinically the most significant of the microsporidia in humans, causing chronic diarrhea wasting and cholangitis in individuals with human immunodeficiency virus infection and AIDS. Little progress on this infection has been made because of the inability to propagate E. bieneusi in vitro and in vivo, which limits the source of parasite spores to the stools of infected human patients. Given the size and shape of the E. bieneusi spores (1.1 to 1.6 by 0.7 to 1.0 microm) and the lack of specific immune reagents, the identification and purification of large quantities of spores from feces are technically challenging. Consequently, diagnosis relies entirely on PCR, a labor-intensive approach that requires highly skilled personnel. We describe a method for the purification of E. bieneusi spores from human stools and the production of rabbit-specific antisera. Spores were purified by a combination of isopycnic Percoll gradient centrifugation and continuous sucrose gradient centrifugation. Specific polyclonal antibodies raised in mice and rabbits reacted by indirect immunofluorescence with E. bieneusi but not with Encephalitozoon spp., Candida albicans, Staphylococcus aureus, Escherichia coli, or other forms present in human stools.

Characterization of Cryptosporidium meleagridis of human origin passaged through different host species.

Cryptosporidium meleagridis, a protozoon first observed in turkeys, has been linked by several investigators to cryptosporidiosis in humans. C. meleagridis is the only known Cryptosporidium species that infects both avian and mammalian species. We describe the successful propagation of C. meleagridis (isolate TU1867), originally purified from a patient with diarrhea, in laboratory animals including chickens, mice, piglets, and calves. TU1867 was readily transmitted from one animal host to another, maintaining genetic homogeneity and stability. The rate of infectivity and virulence of TU1867 for the mammalian species were similar to those of Cryptosporidium parvum. Laboratory propagation of genetically and phenotypically stable and well-characterized reference isolates, representing various Cryptosporidium species, particularly those infectious to humans, will improve considerably the spectrum and quality of laboratory and field investigations on this medically important protozoa.

Structural and biochemical alterations in Giardia lamblia cysts exposed to ozone.

Because of its efficacy in inactivating waterborne protozoan cysts and oocysts, ozone is frequently used for disinfection of drinking water. The effect of ozone on cysts of Giardia lamblia was investigated in gerbils (Meriones unguiculatus), using an infectivity assay by scanning electron microscopy, immunoblotting, and flow cytometry. Cysts recovered from experimentally infected gerbils were exposed to an initial ozone concentration of 1.5 mg/L for 0, 30, 60, and 120 sec. This treatment resulted in a dose-dependent reduction in cysts concentration, loss of infectivity in gerbils, and profound structural modifications to the cyst wall. Exposure for 60 sec or longer resulted in extensive protein degradation and in the disappearance of a cyst wall and a trophozoite antigen.