Evaluating opioid analgesic prescribing limits: A narrative review.

PURPOSE: In response to the opioid crisis, opioid analgesic guidelines and prescribing limits have proliferated. The purpose of this narrative review is to examine evidence from studies evaluating the patient or public health impact of federal and state opioid analgesic prescribing guidelines and laws, describe gaps and challenges in current research, and highlight opportunities for improving future research. METHODS: We focused on evidence from a literature review covering 2013 through 2019. We identified 30 studies evaluating opioid analgesic thresholds based on federal policies and guidelines, state laws, and Medicaid state plans that attempt to influence the course of patient care at or when the limit is exceeded (e.g., prior authorization). RESULTS: Most studies evaluated changes in prescribing or dispensing patterns of opioid analgesics, largely finding decreases in prescribing after policy enactment. Fewer studies evaluated patient or public health outcomes beyond changes in prescribing and dispensing patterns; results were infrequently stratified by potentially important sociodemographic and clinical factors. No studies assessed the potential for adverse patient outcomes for which we have emerging evidence of harms. CONCLUSIONS: We describe knowledge gaps and propose opportunities for future research to sufficiently assess the potential impact and unintended consequences of opioid analgesic prescribing laws, regulations, guidelines, and policies.

Seroepidemiology of helminths and the association with severe malaria among infants and young children in Tanzania.

The disease burden of Wuchereria bancrofti and Plasmodium falciparum malaria is high, particularly in Africa, and co-infection is common. However, the effects of filarial infection on the risk of severe malaria are unknown. We used the remaining serum samples from a large cohort study in Muheza, Tanzania to describe vector-borne filarial sero-reactivity among young children and to identify associations between exposure to filarial parasites and subsequent severe malaria infections. We identified positive filarial antibody responses (as well as positive antibody responses to Strongyloides stercoralis) among infants as young as six months. In addition, we found a significant association between filarial seropositivity at six months of age and subsequent severe malaria. Specifically, infants who developed severe malaria by one year of age were 3.9 times more likely (OR = 3.9, 95% CI: 1.2, 13.0) to have been seropositive for filarial antigen at six months of age compared with infants who did not develop severe malaria.

Spatial epidemiology of blastomycosis hospitalizations: detecting clusters and identifying environmental risk factors.

Blastomycosis is a disease caused by endemic fungi that ranges from severe pulmonary or disseminated to mild or asymptomatic. Environmental factors associated with it are not well described throughout the endemic area. We used the intramural State Inpatient Database from the Agency for Healthcare Research and Quality and ArcMap GIS to identify geographic high-risk clusters of blastomycosis hospitalizations in 13 states in the US endemic regions (AR, IA, IL, IN, KY, LA, MI, MN, MO, MS, OH, TN, and WI). We then used logistic regression to identify risk factors associated with these high-risk clusters. We describe six clusters of counties in which there was an elevated incidence of blastomycosis hospitalizations. We identified maximum mean annual temperature, percentage of persons aged ≥65 years, and mercury and copper soil content as being associated with high-risk clusters. Specifically, the odds of a county being part of a high-risk cluster was associated with increasing percentage of population over age 65, decreasing maximum temperature, increasing mercury, and decreasing copper soil content. Healthcare providers should be aware of these high-risk areas so that blastomycosis can be included, as appropriate, in a differential diagnosis for patients currently or previously residing in these areas.

Incidence and trends of blastomycosis-associated hospitalizations in the United States.

We used the State Inpatient Databases from the United States Agency for Healthcare Research and Quality to provide state-specific age-adjusted blastomycosis-associated hospitalization incidence throughout the entire United States. Among the 46 states studied, states within the Mississippi and Ohio River valleys had the highest age-adjusted hospitalization incidence. Specifically, Wisconsin had the highest age-adjusted hospitalization incidence (2.9 hospitalizations per 100,000 person-years). Trends were studied in the five highest hospitalization incidence states. From 2000 to 2011, blastomycosis-associated hospitalizations increased significantly in Illinois and Kentucky with an average annual increase of 4.4% and 8.4%, respectively. Trends varied significantly by state. Overall, 64% of blastomycosis-associated hospitalizations were among men and the median age at hospitalization was 53 years. This analysis provides a complete epidemiologic description of blastomycosis-associated hospitalizations throughout the endemic area in the United States.

Epidemiology of cryptococcal meningitis in the US: 1997-2009.

Cryptococcal meningitis (CM) causes significant morbidity and mortality globally; however, recent national trends have not been described. Incidence and trends for CM-associated hospitalizations in 18 states were estimated using the Agency for Healthcare and Research Quality (AHRQ) State Inpatient Databases (SID) datasets for 1997 through 2009. We identified 30,840 hospitalizations coded for CM, of which 21.6% were among HIV-uninfected patients. CM in-hospital mortality was significant (12.4% for women and 10.8% for men) with a total of 3,440 deaths over the study period. Co-morbidities of CM coded at increased frequency in HIV-uninfected CM hospitalized populations included hydrocephalus and acute/chronic renal failure as well as possible predispositions including transplantation, combined T and B cell defects, Cushing's syndrome, liver disease and hypogammaglobulinemia. Median hospitalization costs were significant for CM and higher for HIV-uninfected patients (16,803.01 vs. 15,708.07; p<0.0001). Cryptococcal meningitis remains a disease with significant morbidity and mortality in the U.S. and the relative burden among persons without HIV infection is increasing.

Hospitalizations associated with disseminated coccidioidomycosis, Arizona and California, USA.

We analyzed hospitalization databases from Arizona and California for disseminated coccidioidomycosis-associated hospitalizations among immunocompetent persons. Racial/ethnic disease ratios were characterized by a higher incidence of hospitalization among blacks compared with other groups. This finding suggests that HIV infection, AIDS, and primary immune conditions are not a major factor in this disparity.

Spatial clusters of nontuberculous mycobacterial lung disease in the United States.

RATIONALE: Prevalence of pulmonary nontuberculous mycobacterial (PNTM) disease varies by geographic region, yet the factors driving these differences remain largely unknown. OBJECTIVES: To identify spatial clusters of PNTM disease at the county level and to describe environmental and sociodemographic factors predictive of disease. METHODS: PNTM cases identified from a nationally representative sample of Medicare Part B beneficiaries from 1997 to 2007 were geocoded by county and state of residence. County-level PNTM case counts and Medicare population data were then uploaded into SaTScan to identify significant spatial clusters and low-risk areas of disease. High-risk and low-risk counties were then compared to identify significant sociodemographic and environmental differences. MEASUREMENTS AND MAIN RESULTS: We identified seven significant (P < 0.05) clusters of PNTM cases. These high-risk areas encompassed 55 counties in 8 states, including parts of California, Florida, Hawaii, Louisiana, New York, Oklahoma, Pennsylvania, and Wisconsin. Five low-risk areas were also identified, which encompassed 746 counties in 23 states, mostly in the Midwest. Counties in high-risk areas were significantly larger, had greater population densities, and higher education and income levels than low-risk counties. High-risk counties also had higher mean daily potential evapotranspiration levels and percentages covered by surface water, and were more likely to have greater copper and sodium levels in the soil, although lower manganese levels. CONCLUSIONS: Specific environmental factors related to soil and water exposure appear to increase the risk of PNTM infection. Still, given that environmental sources of NTM are ubiquitous and PNTM disease is rare, both host susceptibility and environmental factors must be considered in explaining disease development.

Trends in bronchiectasis among medicare beneficiaries in the United States, 2000 to 2007.

BACKGROUND: Bronchiectasis is a potentially serious condition characterized by permanent and abnormal widening of the airways, the prevalence of which is not well described. We sought to describe the trends, associated conditions, and risk factors for bronchiectasis among adults aged ≥ 65 years. METHODS: A 5% sample of the Medicare outpatient claims database was analyzed for bronchiectasis trends among beneficiaries aged ≥ 65 years from 2000 to 2007. Bronchiectasis was identified using International Classification of Diseases, Ninth Revision, Clinical Modification claim diagnosis codes for acquired bronchiectasis. Period prevalence was used to describe sex- and race/ethnicity-specific rates, and annual prevalence was used to describe trends and age-specific rates. We estimated trends using Poisson regression and odds of bronchiectasis using multivariate logistic regression. RESULTS: From 2000 to 2007, 22,296 people had at least one claim for bronchiectasis. The 8-year period prevalence of bronchiectasis was 1,106 cases per 100,000 people. Bronchiectasis increased by 8.7% per year. We identified an interaction between the number of thoracic CT scans and race/ethnicity; period prevalence varied by a greater degree by number of thoracic CT scans among Asians compared with whites or blacks. Among people with one CT scan, Asians had a 2.5- and 3.9-fold higher period prevalence compared with whites and blacks. CONCLUSIONS: Bronchiectasis prevalence increased significantly from 2000 to 2007 in the Medicare outpatient setting and varied by age, sex, and race/ethnicity. This increase could be due to a true increase in the condition or an increased recognition of previously undiagnosed cases.

Prevalence of nontuberculous mycobacterial lung disease in U.S. Medicare beneficiaries.

RATIONALE: Pulmonary nontuberculous mycobacteria (PNTM) are an important cause of morbidity among older adults in the United States, but national prevalence estimates are lacking. OBJECTIVES: To describe the prevalence and trends of PNTM disease among adults aged 65 years or older throughout the United States. METHODS: A nationally representative 5% sample of Medicare Part B beneficiaries was analyzed from 1997 to 2007. Demographic and medical claims data were compiled and prevalence estimates for PNTM and selected comorbidities were calculated and trends over time evaluated. Logistic regression was used to identify demographic and geographic factors associated with PNTM. MEASUREMENTS AND MAIN RESULTS: From 1997 to 2007, the annual prevalence significantly increased from 20 to 47 cases/100,000 persons, or 8.2% per year. The period prevalence was 112 cases/100,000 persons, although prevalence was twofold higher among Asians/Pacific Islanders than among whites (228 vs. 116 cases/100,000 persons). Western states had the highest period prevalence at 149 cases/100,000 persons, with Hawaii having the highest prevalence at 396 cases/100,000 persons, followed by southeastern states, which had a period prevalence of 131 cases/100,000 persons. PNTM cases had more comorbid conditions than noncases and were 40% more likely to die than noncases. Women were 1.4 times more likely to be a PNTM case than men. Relative to whites, Asians/Pacific Islanders were twice as likely to be a case, whereas blacks were half as likely. CONCLUSIONS: The prevalence of PNTM is increasing across all regions of the United States and among both men and women. Significant racial/ethnic and geographic differences suggest important gene-environment interactions.

Autonomic dysfunction and risk factors associated with Trypanosoma cruzi infection among children in Arequipa, Peru.

Chagas disease affects an estimated 8 million people in Latin America. Infected individuals have 20-30% lifetime risk of developing cardiomyopathy, but more subtle changes in autonomic responses may be more frequent. We conducted a matched case-control study of children in Arequipa, Peru, where triatomine infestation and Trypanosoma cruzi infection are emerging problems. We collected data on home environment, history, physical examination, electrocardiogram, and autonomic testing. Signs of triatomine infestation and/or animals sleeping in the child's room and household members with Chagas disease were associated with increased infection risk. Electrocardiogram findings did not differ between cases and controls. However, compared with control children, infected children had blunted autonomic responses by three different measures, the Valsalva maneuver, the cold pressor test, and the orthostatic test. T. cruzi-infected children show autonomic dysfunction, although the prognostic value of this finding is not clear. Sustained vector control programs are essential to decreasing future T. cruzi infections.

Nontuberculous mycobacterial lung disease prevalence at four integrated health care delivery systems.

RATIONALE: Single-site clinic-based studies suggest an increasing prevalence of pulmonary nontuberculous mycobacteria (NTM) disease, but systematic data are lacking. OBJECTIVES: To describe prevalence and trends for NTM lung disease at four geographically diverse integrated heath care delivery systems in the United States. METHODS: We abstracted mycobacterial culture results from electronic laboratory databases and linked to other datasets containing clinical and demographic information. Possible cases were defined as a single positive NTM pulmonary isolate, and definite cases were defined as two positive sputum cultures, or one positive culture from a bronchoalveolar lavage or lung biopsy. Annual prevalence was calculated using United States census data; average annual prevalence is presented for 2004-2006. Poisson regression models were used to estimate the annual percent change in prevalence. MEASUREMENTS AND MAIN RESULTS: A total of 28,697 samples from 7,940 patients were included in the analysis. Of these, 3,988 (50%) were defined as possible cases, and 1,865 (47%) of these were defined as definite cases. Average annual (2004-2006) site-specific prevalence ranged from 1.4 to 6.6 per 100,000. Prevalence was 1.l- to 1.6-fold higher among women relative to men across sites. The prevalence of NTM lung disease was increasing significantly at the two sites where trends were studied, by 2.6% per year among women and 2.9% per year among men. Among persons aged greater than or equal to 60 years, annual prevalence increased from 19.6 per 100,000 during 1994-1996 to 26.7 per 100,000 during 2004-2006. CONCLUSIONS: The epidemiology of nontuberculous mycobacterial lung disease is changing, with a predominance of women and increasing prevalence at the sites studied.

Trends and burden of bronchiectasis-associated hospitalizations in the United States, 1993-2006.

BACKGROUND: Current data on bronchiectasis prevalence, trends, and risk factors are lacking; such data are needed to estimate the burden of disease and for improved medical care and public health resource allocation. The objective of the present study was to estimate the trends and burden of bronchiectasis-associated hospitalizations in the United States. METHODS: We extracted hospital discharge records containing International Classification of Diseases, 9th Revision, Clinical Modification codes for bronchiectasis (494, 494.0, and 494.1) as any discharge diagnosis from the State Inpatient Databases from the Agency for Healthcare Research and Quality. Discharge records were extracted for 12 states with complete and continuous reporting from 1993 to 2006. RESULTS: The average annual age-adjusted hospitalization rate from 1993 to 2006 was 16.5 hospitalizations per 100,000 population. From 1993 to 2006, the age-adjusted rate increased significantly, with an average annual percentage increase of 2.4% among men and 3.0% among women. Women and persons aged > 60 years had the highest rate of bronchiectasis-associated hospitalizations. The median cost for inpatient care was 7,827 US dollars (USD) (range, 13-543,914 USD). CONCLUSIONS: The average annual age-adjusted rate of bronchiectasis-associated hospitalizations increased from 1993 to 2006. This study furthers the understanding of the impact of bronchiectasis and demonstrates the need for further research to identify risk factors and reasons for the increasing burden.

Spatial patterns in discordant diagnostic test results for Chagas disease: links to transmission hotspots.

Diagnosis of Chagas disease is hindered by discordance between screening and confirmatory test results for Trypanosoma cruzi infection. In periurban Arequipa, Peru, spatial analysis revealed that individuals with discordant test results are spatially clustered in hotspots of T. cruzi transmission, suggesting that discordant results likely represent true infections in this setting.

Chagas disease transmission in periurban communities of Arequipa, Peru.

BACKGROUND: Chagas disease, caused by Trypanosoma cruzi infection, is an urban problem in Arequipa, Peru, and the epidemiology of Chagas disease is likely to be quite different in this area, compared with in rural zones. METHODS: We conducted a serosurvey of 1615 children <18 years old in periurban districts that included hillside shantytowns and slightly more affluent low-lying communities. In addition, 639 adult residents of 1 shantytown were surveyed to provide data across the age spectrum for this community. RESULTS: Of 1615 children, 75 (4.7%) were infected with Trypanosoma cruzi. Infection risk increased by 12% per year of age, and children living in hillside shantytowns were 2.5 times as likely to be infected as were those living in lower-lying communities. However, age-prevalence data from 1 shantytown demonstrated that adults were no more likely to be seropositive than were teenagers; the results of maximum likelihood modeling suggest that T. cruzi transmission began in this community <20 years ago. CONCLUSIONS: The problem of Chagas disease in periurban settings, such as those around Arequipa, must be addressed to achieve elimination of vector-borne T. cruzi transmission. Identification of infected children, vector-control efforts, and education to avoid modifiable risk factors are necessary to decrease the burden of Chagas disease.

Targeted screening strategies to detect Trypanosoma cruzi infection in children.

BACKGROUND: Millions of people are infected with Trypanosoma cruzi, the causative agent of Chagas disease in Latin America. Anti-trypanosomal drug therapy can cure infected individuals, but treatment efficacy is highest early in infection. Vector control campaigns disrupt transmission of T. cruzi, but without timely diagnosis, children infected prior to vector control often miss the window of opportunity for effective chemotherapy. METHODS AND FINDINGS: We performed a serological survey in children 2-18 years old living in a peri-urban community of Arequipa, Peru, and linked the results to entomologic, spatial and census data gathered during a vector control campaign. 23 of 433 (5.3% [95% CI 3.4-7.9]) children were confirmed seropositive for T. cruzi infection by two methods. Spatial analysis revealed that households with infected children were very tightly clustered within looser clusters of households with parasite-infected vectors. Bayesian hierarchical mixed models, which controlled for clustering of infection, showed that a child's risk of being seropositive increased by 20% per year of age and 4% per vector captured within the child's house. Receiver operator characteristic (ROC) plots of best-fit models suggest that more than 83% of infected children could be identified while testing only 22% of eligible children. CONCLUSIONS: We found evidence of spatially-focal vector-borne T. cruzi transmission in peri-urban Arequipa. Ongoing vector control campaigns, in addition to preventing further parasite transmission, facilitate the collection of data essential to identifying children at high risk of T. cruzi infection. Targeted screening strategies could make integration of diagnosis and treatment of children into Chagas disease control programs feasible in lower-resource settings.

Comparative salivary gland transcriptomics of sandfly vectors of visceral leishmaniasis.

BACKGROUND: Immune responses to sandfly saliva have been shown to protect animals against Leishmania infection. Yet very little is known about the molecular characteristics of salivary proteins from different sandflies, particularly from vectors transmitting visceral leishmaniasis, the fatal form of the disease. Further knowledge of the repertoire of these salivary proteins will give us insights into the molecular evolution of these proteins and will help us select relevant antigens for the development of a vector based anti-Leishmania vaccine. RESULTS: Two salivary gland cDNA libraries from female sandflies Phlebotomus argentipes and P. perniciosus were constructed, sequenced and proteomic analysis of the salivary proteins was performed. The majority of the sequenced transcripts from the two cDNA libraries coded for secreted proteins. In this analysis we identified transcripts coding for protein families not previously described in sandflies. A comparative sandfly salivary transcriptome analysis was performed by using these two cDNA libraries and two other sandfly salivary gland cDNA libraries from P. ariasi and Lutzomyia longipalpis, also vectors of visceral leishmaniasis. Full-length secreted proteins from each sandfly library were compared using a stand-alone version of BLAST, creating formatted protein databases of each sandfly library. Related groups of proteins from each sandfly species were combined into defined families of proteins. With this comparison, we identified families of salivary proteins common among all of the sandflies studied, proteins to be genus specific and proteins that appear to be species specific. The common proteins included apyrase, yellow-related protein, antigen-5, PpSP15 and PpSP32-related protein, a 33-kDa protein, D7-related protein, a 39- and a 16.1- kDa protein and an endonuclease-like protein. Some of these families contained multiple members, including PPSP15-like, yellow proteins and D7-related proteins suggesting gene expansion in these proteins. CONCLUSION: This comprehensive analysis allows us the identification of genus- specific proteins, species-specific proteins and, more importantly, proteins common among these different sandflies. These results give us insights into the repertoire of salivary proteins that are potential candidates for a vector-based vaccine.

From transcriptome to immunome: identification of DTH inducing proteins from a Phlebotomus ariasi salivary gland cDNA library.

Delayed-type hypersensitivity (DTH) response to arthropod vector salivary proteins is associated with protection against pathogen transmission. Massive cDNA sequencing, high-throughput DNA plasmid construction and DNA immunisation were used to identify twelve DTH inducing proteins isolated from a Phlebotomus ariasi salivary gland cDNA library. Additionally, nine P. ariasi DNA plasmids produced specific anti-saliva antibodies, four of these showed a Th1 immune response while the other two exhibited a Th2 profile as determined by IgG2a and IgG1 isotype switching, respectively. In order to validate the specificity of sand fly DNA plasmids, mice previously exposed to sand fly saliva were intradermally injected once with selected P. ariasi plasmids and a specific DTH response consisting of infiltration of mononuclear cells in varying proportions was observed at 24 and 48 h. This approach can help to identify DTH inducing proteins that may be related to host protection against vector-borne diseases or other disease agents where cellular immune response is protective.

Aspergillus fumigatus rasA and rasB regulate the timing and morphology of asexual development.

Expression of rasA plays an important role in conidial germination in Aspergillus nidulans. Conidial germination is required to initiate both infection and asexual development in the opportunistic pathogen Aspergillus fumigatus. Therefore, we sought to determine the requirements for Ras proteins in conidial germination and asexual development of A. fumigatus. A second homolog, rasB, has been identified that characterizes a new subclass of Ras genes. Dominant active (DA) and dominant negative (DN) mutations of each gene were introduced into protoplasts as transgenes. DArasA expression led to reduced conidiation, malformed conidiophores, and altered mitotic progression, whereas expression of DNrasA caused a significant reduction in the rate of conidial germination. In contrast, expression of DNrasB slightly delayed the initiation of germination and caused the development of conidiophores in submerged culture. DArasB expression led to reduced conidiation. RasA and RasB appear to play different, but overlapping, roles in the vegetative growth and asexual development of A. fumigatus.