Modeling the evolution of C4 photosynthesis.

The prediction and verification of adaptive trajectories on macroevolutionary timescales have rarely been achieved for complex biological systems. Employing a model linking biological information at multiple scales, Heckmann et al. simulate likely sequences of evolutionary changes from C3 to C4 photosynthesis biochemistry.

Histoplasmosis-related Healthcare Use, Diagnosis, and Treatment in a Commercially Insured Population, United States.

BACKGROUND: Infections with Histoplasma can range from asymptomatic to life-threatening acute pulmonary or disseminated disease. Histoplasmosis can be challenging to diagnose and is widely underrecognized. We analyzed insurance claims data to better characterize histoplasmosis testing and treatment practices and its burden on patients. METHODS: We used the IBM MarketScan Research Databases to identify patients with histoplasmosis (International Classification of Diseases, Ninth Revision, Clinical Modification codes 115.00-115.99) during 2012-2014. We analyzed claims in the 3 months before to the 1 year after diagnosis and examined differences between patients with probable (hospitalized or >1 outpatient visit) and suspected (1 outpatient visit) histoplasmosis. RESULTS: Among 1935 patients (943 probable, 992 suspected), 54% had codes for symptoms or findings consistent with histoplasmosis and 35% had ≥2 healthcare visits in the 3 months before diagnosis. Overall, 646 (33%) had any fungal-specific laboratory test: histoplasmosis antibody test (n = 349 [18%]), Histoplasma antigen test (n = 349 [18%]), fungal smear (n = 294 [15%]), or fungal culture (n = 223 [12%]); 464 (24%) had a biopsy. Forty-nine percent of probable patients and 10% of suspected patients were prescribed antifungal medication in the outpatient setting. In total, 19% were hospitalized. Patients' last histoplasmosis-associated healthcare visits occurred a median of 6 months after diagnosis. CONCLUSIONS: Some histoplasmosis patients experienced severe disease, apparent diagnostic delays, and prolonged illness, whereas other patients lacked symptoms and were likely diagnosed incidentally (eg, via biopsy). Low rates of histoplasmosis-specific testing also suggest incidental diagnoses and low provider suspicion, highlighting the need for improved awareness about this disease.

Knowledge of Infectious Disease Specialists Regarding Aspergillosis Complicating Influenza, United States.

In an online survey, we found that nearly one fifth of physicians in the United States who responded had seen or heard about a case of invasive pulmonary aspergillosis after severe influenza at their institution. However, <10% routinely used galactomannan testing to test for this fungus in patients with severe influenza.

Antibiotic and antifungal treatment among persons with confirmed coccidioidomycosis - Southern California, 2011.

We investigated coccidioidomycosis testing and treatment patterns among persons in an integrated healthcare delivery system to identify gaps in diagnosis and treatment. Coccidioidomycosis diagnosis delays were common. Among persons who tested positive, 70% were prescribed antibiotics before positive coccidioidomycosis tests. Antibiotic treatment decreased and antifungal treatment increased after positive testing.

Estimation of Direct Healthcare Costs of Fungal Diseases in the United States.

BACKGROUND: Fungal diseases range from relatively-minor superficial and mucosal infections to severe, life-threatening systemic infections. Delayed diagnosis and treatment can lead to poor patient outcomes and high medical costs. The overall burden of fungal diseases in the United States is challenging to quantify, because they are likely substantially underdiagnosed. METHODS: To estimate the total, national, direct medical costs associated with fungal diseases from a healthcare payer perspective, we used insurance claims data from the Truven Health MarketScan 2014 Research Databases, combined with hospital discharge data from the 2014 Healthcare Cost and Utilization Project National Inpatient Sample and outpatient visit data from the 2005-2014 National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey. All costs were adjusted to 2017 dollars. RESULTS: We estimate that fungal diseases cost more than $7.2 billion in 2017, including $4.5 billion from 75055 hospitalizations and $2.6 billion from 8993230 outpatient visits. Hospitalizations for Candida infections (n = 26735, total cost $1.4 billion) and Aspergillus infections (n = 14820, total cost $1.2 billion) accounted for the highest total hospitalization costs of any disease. Over half of outpatient visits were for dermatophyte infections (4981444 visits, total cost $802 million), and 3639037 visits occurred for non-invasive candidiasis (total cost $1.6 billion). CONCLUSIONS: Fungal diseases impose a considerable economic burden on the healthcare system. Our results likely underestimate their true costs, because they are underdiagnosed. More comprehensive estimates of the public health impact of these diseases are needed to improve their recognition, prevention, diagnosis, and treatment.

Hurricane-Associated Mold Exposures Among Patients at Risk for Invasive Mold Infections After Hurricane Harvey - Houston, Texas, 2017.

In August 2017, Hurricane Harvey caused unprecedented flooding and devastation to the Houston metropolitan area (1). Mold exposure was a serious concern because investigations after Hurricanes Katrina and Rita (2005) had documented extensive mold growth in flood-damaged homes (2,3). Because mold exposure can cause serious illnesses known as invasive mold infections (4,5), and immunosuppressed persons are at high risk for these infections (6,7), several federal agencies recommend that immunosuppressed persons avoid mold-contaminated sites (8,9). To assess the extent of exposure to mold and flood-damaged areas among persons at high risk for invasive mold infections after Hurricane Harvey, CDC and Texas health officials conducted a survey among 103 immunosuppressed residents in Houston. Approximately half of the participants (50) engaged in cleanup of mold and water-damaged areas; these activities included heavy cleanup (23), such as removing furniture or removing drywall, or light cleanup (27), such as wiping down walls or retrieving personal items. Among immunosuppressed persons who performed heavy cleanup, 43% reported wearing a respirator, as did 8% who performed light cleanup. One participant reported wearing all personal protective equipment (PPE) recommended for otherwise healthy persons (i.e., respirator, boots, goggles, and gloves). Immunosuppressed residents who are at high risk for invasive mold infections were exposed to mold and flood-damaged areas after Hurricane Harvey; recommendations from health care providers to avoid exposure to mold and flood-damaged areas could mitigate the risk to immunosuppressed persons.

Recognition of Azole-Resistant Aspergillosis by Physicians Specializing in Infectious Diseases, United States.

Infections caused by pan-azole-resistant Aspergillus fumigatus strains have emerged in Europe and recently in the United States. Physicians specializing in infectious diseases reported observing pan-azole-resistant infections and low rates of susceptibility testing, suggesting the need for wider-scale testing.

Detection of TR34/L98H CYP51A Mutation through Passive Surveillance for Azole-Resistant Aspergillus fumigatus in the United States from 2015 to 2017.

The emergence of azole-resistant Aspergillus fumigatus has become a clinical problem in many parts of the world. Several amino acid mutations in the azole target protein Cyp51Ap contribute to this resistance, with the most concerning being the environmentally derived TR34/L98H and TR46/Y121F/T289A mutations. Here, we performed passive surveillance to assess a sample of the A. fumigatus population in the United States for the presence of these mutations. We found 1.4% of those isolates to exhibit elevated MIC via broth microdilution, and five of those isolates harbored the TR34/L98H mutation.

Multidrug-Resistant Aspergillus fumigatus Carrying Mutations Linked to Environmental Fungicide Exposure - Three States, 2010-2017.

The environmental mold Aspergillus fumigatus is the primary cause of invasive aspergillosis. In patients with high-risk conditions, including stem cell and organ transplant recipients, mortality exceeds 50%. Triazole antifungals have greatly improved survival (1); however, triazole-resistant A. fumigatus infections are increasingly reported worldwide and are associated with increased treatment failure and mortality (2). Of particular concern are resistant A. fumigatus isolates carrying either TR34/L98H or TR46/Y121F/T289A genetic resistance markers, which have been associated with environmental triazole fungicide use rather than previous patient exposure to antifungals (3,4). Reports of these triazole-resistant A. fumigatus strains have become common in Europe (2,3), but U.S. reports are limited (5). Because of the risk posed to immunocompromised patients, understanding the prevalence of such isolates in patients is important to guide clinical and public health decision-making. In 2011, CDC initiated passive laboratory monitoring for U.S. triazole-resistant A. fumigatus isolates through outreach to clinical laboratories. This system identified five TR34/L98H isolates collected from 2016 to 2017 (6), in addition to two other U.S. isolates collected in 2010 and 2014 and reported in 2015 (5). Four of these seven isolates were reported from Pennsylvania, two from Virginia, and one from California. Three isolates were collected from patients with invasive pulmonary aspergillosis, and four patients had no known previous triazole exposure. A. fumigatus resistant to all triazole medications is emerging in the United States, and clinicians and public health personnel need to be aware that resistant infections are possible even in patients not previously exposed to these medications.

Giardiasis Diagnosis and Treatment Practices Among Commercially Insured Persons in the United States.

Background: Giardiasis, the most common enteric parasitic infection in the United States, causes an estimated 1.2 million episodes of illness annually. Published clinical recommendations include readily available Giardia-specific diagnostic testing and antiparasitic drugs. We investigated sequences of giardiasis diagnostic and treatment events using MarketScan, a large health insurance claims database. Methods: We created a longitudinal cohort of 2995 persons diagnosed with giardiasis (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 007.1) from 2006 to 2010, and analyzed claims occurring 90 days before to 90 days after initial diagnosis. We evaluated differences in number and sequence of visits, diagnostic tests, and prescriptions by age group (children 1-17 years, adults 18-64 years) using χ2 tests and data visualization software. Results: Among 2995 patients (212433 claims), 18% had a Giardia-specific test followed by or concurrent with an effective antiparasitic drug, without ineffective antibiotics. Almost two-thirds of patients had an antiparasitic and 27% had an antibiotic during the study window. Compared with children, adults more often had ≥3 visits before diagnosis (19% vs 15%; P = .02). Adults were also less likely to have a Giardia-specific diagnostic test (48% vs 58%; P < .001) and more likely to have an antibiotic prescription (28% vs 25%; P = .04). When Giardia-specific tests and antiparasitic and antibiotic prescriptions were examined, pediatric clinical event sequences most frequently began with a Giardia-specific test, whereas adult sequences most frequently began with an antiparasitic prescription. Conclusions: Giardiasis care infrequently follows all aspects of clinical recommendations. Multiple differences between pediatric and adult care, despite age-agnostic recommendations, suggest opportunities for provider education or tailored guidance.

An evolutionarily conserved RNase-based mechanism for repression of transcriptional positive autoregulation.

It is known that environmental context influences the degree of regulation at the transcriptional and post-transcriptional levels. However, the principles governing the differential usage and interplay of regulation at these two levels are not clear. Here, we show that the integration of transcriptional and post-transcriptional regulatory mechanisms in a characteristic network motif drives efficient environment-dependent state transitions. Through phenotypic screening, systems analysis, and rigorous experimental validation, we discovered an RNase (VNG2099C) in Halobacterium salinarum that is transcriptionally co-regulated with genes of the aerobic physiologic state but acts on transcripts of the anaerobic state. Through modelling and experimentation we show that this arrangement generates an efficient state-transition switch, within which RNase-repression of a transcriptional positive autoregulation (RPAR) loop is critical for shutting down ATP-consuming active potassium uptake to conserve energy required for salinity adaptation under aerobic, high potassium, or dark conditions. Subsequently, we discovered that many Escherichia coli operons with energy-associated functions are also putatively controlled by RPAR indicating that this network motif may have evolved independently in phylogenetically distant organisms. Thus, our data suggest that interplay of transcriptional and post-transcriptional regulation in the RPAR motif is a generalized principle for efficient environment-dependent state transitions across prokaryotes.

Divergence in DNA photorepair efficiency among genotypes from contrasting UV radiation environments in nature.

Populations of organisms routinely face abiotic selection pressures, and a central goal of evolutionary biology is to understand the mechanistic underpinnings of adaptive phenotypes. Ultraviolet radiation (UVR) is one of earth's most pervasive environmental stressors, potentially damaging DNA in any organism exposed to solar radiation. We explored mechanisms underlying differential survival following UVR exposure in genotypes of the water flea Daphnia melanica derived from natural ponds of differing UVR intensity. The UVR tolerance of a D. melanica genotype from a high-UVR habitat depended on the presence of visible and UV-A light wavelengths necessary for photoenzymatic repair of DNA damage, a repair pathway widely shared across the tree of life. We then measured the acquisition and repair of cyclobutane pyrimidine dimers, the primary form of UVR-caused DNA damage, in D. melanica DNA following experimental UVR exposure. We demonstrate that genotypes from high-UVR habitats repair DNA damage faster than genotypes from low-UVR habitats in the presence of visible and UV-A radiation necessary for photoenzymatic repair, but not in dark treatments. Because differences in repair rate only occurred in the presence of visible and UV-A radiation, we conclude that differing rates of DNA repair, and therefore differential UVR tolerance, are a consequence of variation in photoenzymatic repair efficiency. We then rule out a simple gene expression hypothesis for the molecular basis of differing repair efficiency, as expression of the CPD photolyase gene photorepair did not differ among D. melanica lineages, in both the presence and absence of UVR.

Surveillance for Waterborne Disease Outbreaks Associated with Drinking Water - United States, 2011-2012.

Advances in water management and sanitation have substantially reduced waterborne disease in the United States, although outbreaks continue to occur. Public health agencies in the U.S. states and territories* report information on waterborne disease outbreaks to the CDC Waterborne Disease and Outbreak Surveillance System (http://www.cdc.gov/healthywater/surveillance/index.html). For 2011-2012, 32 drinking water-associated outbreaks were reported, accounting for at least 431 cases of illness, 102 hospitalizations, and 14 deaths. Legionella was responsible for 66% of outbreaks and 26% of illnesses, and viruses and non-Legionella bacteria together accounted for 16% of outbreaks and 53% of illnesses. The two most commonly identified deficiencies† leading to drinking water-associated outbreaks were Legionella in building plumbing§ systems (66%) and untreated groundwater (13%). Continued vigilance by public health, regulatory, and industry professionals to identify and correct deficiencies associated with building plumbing systems and groundwater systems could prevent most reported outbreaks and illnesses associated with drinking water systems.

Outbreaks Associated With Environmental and Undetermined Water Exposures - United States, 2011-2012.

Exposures to contaminated water can lead to waterborne disease outbreaks associated with various sources, including many that are classified and reported separately as drinking water or recreational water. Waterborne disease outbreaks can also involve a variety of other exposures (e.g., consuming water directly from backcountry or wilderness streams, or inhaling aerosols from cooling towers and ornamental fountains). Additionally, outbreaks might be epidemiologically linked to multiple water sources or may not have a specific water source implicated.

Community Knowledge, Attitudes, and Practices Regarding Ebola Virus Disease - Five Counties, Liberia, September-October, 2014.

As of July 1, 2015, Guinea, Liberia, and Sierra Leone have reported a total of 27,443 confirmed, probable, and suspected Ebola virus disease (Ebola) cases and 11,220 deaths. Guinea and Sierra Leone have yet to interrupt transmission of Ebola virus. In January, 2016, Liberia successfully achieved Ebola transmission-free status, with no new Ebola cases occurring during a 42-day period; however, new Ebola cases were reported beginning June 29, 2015. Local cultural practices and beliefs have posed challenges to disease control, and therefore, targeted, timely health messages are needed to address practices and misperceptions that might hinder efforts to stop the spread of Ebola. As early as September 2014, Ebola spread to most counties in Liberia. To assess Ebola-related knowledge, attitudes, and practices (KAP) in the community, CDC epidemiologists who were deployed to the counties (field team), carried out a survey conducted by local trained interviewers. The survey was conducted in September and October 2014 in five counties in Liberia with varying cumulative incidence of Ebola cases. Survey results indicated several findings. First, basic awareness of Ebola was high across all surveyed populations (median correct responses = 16 of 17 questions on knowledge of Ebola transmission; range = 2-17). Second, knowledge and understanding of Ebola symptoms were incomplete (e.g., 61% of respondents said they would know if they had Ebola symptoms). Finally, certain fears about the disease were present: >90% of respondents indicated a fear of Ebola patients, >40% a fear of cured patients, and >50% a fear of treatment units (expressions of this last fear were greater in counties with lower Ebola incidence). This survey, which was conducted at a time when case counts were rapidly increasing in Liberia, indicated limited knowledge of Ebola symptoms and widespread fear of Ebola treatment units despite awareness of communication messages. Continued efforts are needed to address cultural practices and beliefs to interrupt Ebola transmission.

Large Outbreak of Botulism Associated with a Church Potluck Meal--Ohio, 2015.

On April 21, 2015, the Fairfield Medical Center (FMC) and Fairfield Department of Health contacted the Ohio Department of Health (ODH) about a patient suspected of having botulism in Fairfield County, Ohio. Botulism is a severe, potentially fatal neuroparalytic illness.* A single case is a public health emergency, because it can signal an outbreak. Within 2 hours of health department notification, four more patients with similar clinical features arrived at FMC's emergency department. Later that afternoon, one patient died of respiratory failure shortly after arriving at the emergency department. All affected persons had eaten at the same widely attended church potluck meal on April 19. CDC's Strategic National Stockpile sent 50 doses of botulinum antitoxin to Ohio. FMC, the Fairfield Department of Health, ODH, and CDC rapidly responded to confirm the diagnosis, identify and treat additional patients, and determine the source.

Model organisms retain an "ecological memory" of complex ecologically relevant environmental variation.

Although tractable model organisms are essential to characterize the molecular mechanisms of evolution and adaptation, the ecological relevance of their behavior is not always clear because certain traits are easily lost during long-term laboratory culturing. Here, we demonstrate that despite their long tenure in the laboratory, model organisms retain "ecological memory" of complex environmental changes. We have discovered that Halobacterium salinarum NRC-1, a halophilic archaeon that dominates microbial communities in a dynamically changing hypersaline environment, simultaneously optimizes fitness to total salinity, NaCl concentration, and the [K]/[Mg] ratio. Despite being maintained under controlled conditions over the last 50 years, peaks in the three-dimensional fitness landscape occur in salinity and ionic compositions that are not replicated in laboratory culturing but are routinely observed in the natural hypersaline environment of this organism. Intriguingly, adaptation to variations in ion composition was associated with differential regulation of anaerobic metabolism genes, suggesting an intertwined relationship between responses to oxygen and salinity. Our results suggest that the ecological memory of complex environmental variations is imprinted in the networks for coordinating multiple cellular processes. These coordination networks are also essential for dealing with changes in other physicochemically linked factors present during routine laboratory culturing and, hence, retained in model organisms.

Assessment of ebola virus disease, health care infrastructure, and preparedness - four counties,Southeastern Liberia, august 2014.

Ebola virus disease (Ebola) is a multisystem disease caused by a virus of the genus Ebolavirus. In late March 2014, Ebola cases were described in Liberia, with epicenters in Lofa County and later in Montserrado County. While information about case burden and health care infrastructure was available for the two epicenters, little information was available about remote counties in southeastern Liberia. Over 9 days, August 6-14, 2014, Ebola case burden, health care infrastructure, and emergency preparedness were assessed in collaboration with the Liberian Ministry of Health and Social Welfare in four counties in southeastern Liberia: Grand Gedeh, Grand Kru, River Gee, and Maryland. Data were collected by health care facility visits to three of the four county referral hospitals and by unstructured interviews with county and district health officials, hospital administrators, physicians, nurses, physician assistants, and health educators in all four counties. Local burial practices were discussed with county officials, but no direct observation of burial practices was conducted. Basic information about Ebola surveillance and epidemiology, case investigation, contact tracing, case management, and infection control was provided to local officials.

Using a medication event monitoring system to evaluate self-report and pill count for determining treatment completion with self-administered, once-weekly isoniazid and rifapentine.

BACKGROUND: Treatment completion is essential for the effectiveness of any latent tuberculosis infection (LTBI) regimen. The Tuberculosis Trials Consortium (TBTC) Study 33 (iAdhere) combined self-report and pill counts - standard of care (SOC) with a medication event monitoring system (MEMS) to determine treatment completion for 12-dose once-weekly isoniazid and rifapentine (3HP). Understanding the performance of SOC relative to MEMS can inform providers and suggest when interventions may be applied to optimize LTBI treatment completion. METHOD: iAdhere randomized participants to directly observed therapy (DOT), SAT, or SAT with text reminders in Hong Kong, South Africa, Spain and the United States (U.S.). This post-hoc secondary analysis evaluated treatment completion in both SAT arms, and compared completion based on SOC with MEMS to completion based on SOC only. Treatment completion proportions were compared. Characteristics associated with discordance between SOC and SOC with MEMS were identified. RESULTS: Overall 80.8% of 665 participants completed treatment per SOC, compared to 74.7% per SOC with MEMS, a difference of 6.1% (95%CI: 4.2%, 7.8%). Among U.S. participants only, this difference was 3.3% (95% CI: 1.8%, 4.9%). Differences in completion was 3.1% (95% CI: -1.1%, 7.3%) in Spain, and 36.8% (95% CI: 24.3%, 49.4%) in South Africa. There was no difference in Hong Kong. CONCLUSION: When used for monitoring 3HP, SOC significantly overestimated treatment completion in U.S. and South Africa. However, SOC still provides a reasonable estimate of treatment completion of the 3HP regimen, in U.S., Spain, and Hong Kong.