Trends in EMR for nonmalignant colorectal polyps in the United States.

BACKGROUND AND AIMS: Although most large nonpedunculated colorectal lesions can be safely and efficaciously removed using EMR, the use of colectomy for benign colorectal lesions appears to be increasing. The reason(s) is unclear. We aimed to determine the use and adverse events of EMR in the United States. METHODS: We used Optum's de-identified Clinformatics Data Mart Database (2003-2016), a database from a large national insurance provider, to identify all colonoscopies performed with either EMR or simple polypectomy on adult patients from January 1, 2011 to December 31, 2015. We measured time trends, regional variation, and adverse event rates. We assessed risk factors for adverse events using multivariate logistic regression. RESULTS: The rate of EMR use in the US increased from 1.62% of all colonoscopies in 2011 to 2.48% of colonoscopies in 2015 (P < .001). There were, however, significant regional differences in the use of EMRs, from 2.4% of colonoscopies in the western United States to 2.0% of colonoscopies in the southern United States. Between 2011 and 2015, we found stable rates of perforation, GI bleeding (GIB), infections, and cardiac adverse events and decreasing rates of admissions after EMR. In our multivariate model, EMR was an independent risk factor for adverse events, albeit the rates of adverse events were low (1.35% GIB, .22% perforation). CONCLUSIONS: Use of EMR is rising in the United States, although there is significant regional variation. The rates of adverse events after EMR and polypectomies were low and stable, confirming the continued safety of EMR procedures. A better understanding of the regional barriers and facilitators may improve the use of EMR as the standard management for benign colorectal lesions throughout the United States.

Cytomegalovirus infection is associated with worse outcomes in inflammatory bowel disease hospitalizations nationwide.

BACKGROUND: Cytomegalovirus (CMV) infection may complicate ulcerative colitis (UC) or Crohn's disease (CD) hospitalizations. Studies examining this relationship are often single-center examining short time periods. AIMS: To quantify the prevalence of CMV and its impact on outcomes among UC and CD hospitalizations over time using nationwide administrative databases. METHODS: The National Inpatient Sample and Nationwide Readmissions Database were analyzed to calculate CMV prevalence per 1000 UC and CD hospitalizations between 1998 and 2014. Univariable and multivariable logistic and linear regression were used to assess CMV's association with outcomes. Separate analyses examined effects from the introduction of anti-TNF therapy in UC in 2005, CD anatomic extent, and Clostridioides difficile infection. RESULTS: Among UC, from 1998 to 2014, the prevalence of CMV infection rose from 1.4 to 6.3 per 1000 UC hospitalizations (p < 0.001), although this increase was not statistically significant for the years 2006 to 2014 (p = 0.07). Among CD, prevalence rose from 0.3 to 1.8 per 1000 CD hospitalizations (p < 0.001) from 1998 to 2014. CMV was independently associated with increased inpatient mortality (UC: odds ratio (OR) 2.3, 95% confidence interval (CI) 1.2-4.5; CD: OR 4.6, CI 1.5-13.7), colectomy in UC (OR 2.5, CI 1.9-3.3), and higher length of stay and costs. CONCLUSION: CMV infection's prevalence among UC and CD hospitalizations is rising over time, but may have slowed after 2005 in UC. CMV is independently associated with increased inpatient mortality, length of stay, and hospital charges in UC and CD and with colectomy in UC.

Antiviral therapy and the development of osteopenia/osteoporosis among Asians with chronic hepatitis B.

BACKGROUND: Recent studies have suggested a potential increase in the incidence of osteoporosis for patients receiving tenofovir disoproxil fumarate (TDF), but this issue remains controversial. METHODS: The retrospective cohort study of 1224 Asian chronic hepatitis B (CHB) patients greater than 18 years without baseline osteopenia/osteoporosis seen at four US centers from 2008 to 2016. Patients were categorized into three groups-treatment-naive patients who initiated therapy with TDF (1) or entecavir (ETV) (2), or untreated patients (3). Patients were followed until the development of osteopenia/osteoporosis or end of the study. RESULTS: Of the 1224 study patients, 276 were treated with TDF, 335 with ETV, and 613 were untreated. The prevalence of cirrhosis was lower for untreated patients (2.6% vs 16.3% for TDF and 17.6% for ETV; P < 0.001). The 8-year cumulative incidence rate of osteopenia/osteoporosis was 13.17% for TDF, 15.09% for ETV, and 10.17% for untreated patients, with no statistically significant difference among the three groups ( P = 0.218). On multivariate Cox regression controlling for demographics, osteoporosis risk factors, albumin, and hepatitis B virus (HBV) DNA levels, neither TDF (adjusted hazard ratio [HR] = 0.74; 95% confidence interval [CI]: 0.34 and 1.59) nor ETV (adjusted HR = 0.98; 95% CI: 0.51 and 1.90) were associated with increased osteopenia/osteoporosis risk compared with untreated patients. CONCLUSIONS: Our retrospective study suggests that there is no significant increase in the incidence of osteopenia/osteoporosis for patients with CHB treated with TDF or ETV during a median follow-up of about 4 to 5 years. However, further study with longer follow-up is needed as an anti-HBV therapy, which is often lifelong or long-term and the development of osteopenia/osteoporosis can be a slow process.

Peripartum Maternal Hepatitis B Care in a US Nationwide Data Set.

BACKGROUND: Hepatitis B virus (HBV) screening during pregnancy is standard of care to prevent vertical transmission to infants, yet the mothers themselves may not receive appropriate follow-up. GOALS: Using a national database, we sought to determine rates of maternal peripartum follow-up with a HBV specialist and identify factors associated with a lack of follow-up. MATERIALS AND METHODS: We identified women who delivered in 2000 to 2012 and were diagnosed with HBV according to International Classification of Diseases-9 codes using a national database (Optum) derived from commercial insurance claims with ∼46 million members ages 0 to 64 in all 50 states. Our primary outcome was follow-up during or after pregnancy with a HBV specialist (gastroenterology/infectious diseases). RESULTS: The prevalence of HBV was 0.27% (2558/959,747 pregnancies), and median follow-up was 45 months. Only 21% of women had peripartum HBV specialist follow-up. On multivariable regression, predictors of peripartum follow-up at 1-year included younger age [odds ratio (OR), 0.97/y; 95% confidence interval (CI), 0.94, 0.99], Asian race/ethnicity (OR, 1.56 vs. white; 95% CI, 1.13, 2.17), and residing in the Northeast (OR, 1.70; 95% CI, 1.09, 2.66) and Midwest (OR, 1.73; 95% CI, 1.07, 2.81) versus West. Predictors of testing for HBV DNA and alanine aminotransferase at 1 year included Asian race (OR, 1.72; 95% CI, 1.23, 2.41), a primary care physician visit within 2 years of delivery (OR, 1.63; 95% CI, 1.19, 2.22), and peripartum HBV specialist follow-up within 1 year (OR, 15.68; 95% CI, 11.38, 21.60). CONCLUSIONS: Maternal HBV specialist follow-up rates were extremely low in this large, diverse cohort representing all United States regions. Referral to a HBV specialist was the strongest predictor of appropriate postpartum HBV laboratory testing. Follow-up rates may be even lower in uninsured populations.

Correction to: Hospital Cirrhosis Volume and Readmission in Patients with Cirrhosis in California.

The original version of the article unfortunately contained errors in 'Severity of illness' and 'Hospital characteristics' entries of Table 1. Corrected version of Table 1 is given below.

Hospital Cirrhosis Volume and Readmission in Patients with Cirrhosis in California.

BACKGROUND: Patients with cirrhosis are at high readmission risk. Using a large statewide database, we evaluated the effect of hospital cirrhosis-related patient volume on 30-day readmissions in patients with cirrhosis. METHODS: We conducted a retrospective study of the Healthcare Cost and Utilization Project State Inpatient Database for adult patients with cirrhosis, as defined by International Classification of Diseases, Ninth Revision (ICD-9) codes, hospitalized in California between 2009 and 2011. Multivariable logistic regression analysis was performed to evaluate the effect of hospital volume on 30-day readmissions. RESULTS: A total of 69,612 patients with cirrhosis were identified in 405 hospitals; 24,062 patients were discharged from the top 10% of hospitals (N = 41) by cirrhosis volume, and 45,550 patients in the bottom 90% (N = 364). Compared with higher-volume centers, lower-volume hospitals cared for patients with similar average Quan-Charlson-Deyo (QCD) comorbidity scores (6.54 vs. 6.68), similar proportion of hepatitis B and fatty liver disease, lower proportion of hepatitis C (34.8 vs. 41.5%) but greater proportion of alcoholic liver disease (53.1 vs. 47.4%). Multivariable logistic regression analysis demonstrated admission to a lower-volume hospital did not predict 30-day readmission (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.92-1.01) after adjusting for sociodemographics, QCD score, cirrhosis severity, and hospital characteristics. Instead, liver transplant center status significantly decreased the risk of readmission (OR 0.87, 95% CI 0.80-0.94). Ascites, hepatic encephalopathy, hepatocellular carcinoma, higher QCD, and presence of alcoholic liver disease and hepatitis C were also independent predictors. CONCLUSIONS: Readmissions within 30 days were common among patients with cirrhosis hospitalized in California. While hospital cirrhosis volume did not predict 30-day readmissions, liver transplant center status was protective of readmissions. Medically complicated patients with cirrhosis at hospitals without liver transplant centers may benefit from additional support to prevent readmission.

Peripartum Care for Mothers Diagnosed with Hepatitis B During Pregnancy: A Survey of Provider Practices.

Objectives Hepatitis B (HBV) remains a significant public health burden, despite effective therapy. Routine HBV screening is recommended during pregnancy to reduce the risk of vertical transmission, but the rates of follow-up care peri-partum are low. The aim of this study was to evaluate physician practices and knowledge regarding HBV in women diagnosed perinatally. Methods A survey was distributed to obstetricians and midwives within the Partners HealthCare system at Brigham and Women's Hospital and Massachusetts General Hospital. Results Of 118 survey respondents (response rate 56%), 97% reported that they always tested for hepatitis B, and 77% referred new diagnoses of HBV during pregnancy to a HBV specialist for further care. Only 10% of respondents reported that there was formal referral mechanism in place to facilitate follow-up care for mothers diagnosed with hepatitis B infection. 91% of survey respondents selected hepatitis B surface antigen as the correct screening test, and 76% selected hepatitis B immune globulin with vaccination for the newborn as the correct prophylaxis regimen. Only 40 and 51% of respondents accurately identified serologies that were consistent with acute and chronic infection, respectively. Conclusions for Practice Routine screening for HBV in this population presents an important opportunity to identify cases and to reduce the public health burden of this disease. Providers were somewhat knowledgeable about HBV, but the lack of formal referral mechanism may explain why HBV follow-up is suboptimal in this healthcare system. Supplemental provider education and formal linkage to care programs may increase rates of follow-up HBV care.

Management of Chronic Hepatitis B in Pregnancy.

Chronic hepatitis B virus (HBV) infection due to mother-to-child transmission during the perinatal period remains an important global health problem. Despite standard passive-active immunoprophylaxis with hepatitis B immunoglobulin and hepatitis B vaccine in neonates, up to 8.5% of newborns still acquire HBV infection. Thus, management of chronic HBV during pregnancy and strategies to prevent mother-to-child transmission are important steps in eradicating or reducing the global burden of chronic HBV infection. To date, the management of HBV infection in pregnancy still needs careful attention because of some controversial aspects, including the influence of pregnancy on the course of HBV replication, safety of antiviral prophylaxis with nucleus(t)ide analogs, postpartum flares of hepatitis after delivery, and the safety of breastfeeding. In this review, we highlight these important issues of preventive strategies in the perinatal period.

Postpartum Laboratory Follow-up in Women With Hepatitis B in Massachusetts From 2007 to 2012.

GOALS: To determine postpartum hepatitis B virus (HBV) laboratory testing rates and identify factors associated with a lack of follow-up testing in Massachusetts. BACKGROUND: Screening for HBV infection in pregnant women is standard of care. Guidelines recommend that patients with chronic HBV have ongoing care and laboratory testing, but little is known about postpartum maternal HBV care outcomes. STUDY: We conducted a retrospective cohort study using Massachusetts Virtual Epidemiologic Network, an electronic public health surveillance system maintained by the Massachusetts Department of Public Health. We identified women who tested hepatitis B surface antigen positive during their first reported (index) pregnancy in Massachusetts from 2007 to 2012 and measured HBV-related laboratory tests reported to Massachusetts Department of Public Health during and after pregnancy. RESULTS: We identified 983 hepatitis B surface antigen positive pregnant women. Half (492/983) did not have evidence of additional postpartum HBV laboratory testing following their index pregnancy. Women who had postpartum laboratory tests reported were younger [mean age (SD): 29 (5.3) vs. 31 (5.5) y, P=0.0001] and more likely to have >1 pregnancy during the study period (41% vs. 1%, P<0.0001). There were no differences in race, ethnicity, and US born status. On multivariable logistic regression, older age predicted a lower likelihood of having postpartum laboratory testing (odds ratio, 0.77; 95% confidence interval, 0.70-0.90). CONCLUSIONS: Postpartum maternal HBV follow-up laboratory testing occurred in only half of Massachusetts women and did not vary by race, ethnicity, or US born status. Our results were limited to a single state surveillance database, which likely underestimates the number of tests ordered.

Steroid use in acute liver failure.

UNLABELLED: Drug-induced and indeterminate acute liver failure (ALF) might be due to an autoimmune-like hepatitis that is responsive to corticosteroid therapy. The aim of this study was to evaluate whether corticosteroids improve survival in fulminant autoimmune hepatitis, drug-induced, or indeterminate ALF, and whether this benefit varies according to the severity of illness. We conducted a retrospective analysis of autoimmune, indeterminate, and drug-induced ALF patients in the Acute Liver Failure Study Group from 1998-2007. The primary endpoints were overall and spontaneous survival (SS, survival without transplant). In all, 361 ALF patients were studied, 66 with autoimmune (25 steroids, 41 no steroids), 164 with indeterminate (21 steroids, 143 no steroids), and 131 with drug-induced (16 steroids, 115 no steroids) ALF. Steroid use was not associated with improved overall survival (61% versus 66%, P = 0.41), nor with improved survival in any diagnosis category. Steroid use was associated with diminished survival in certain subgroups of patients, including those with the highest quartile of the Model for Endstage Liver Disease (MELD) (>40, survival 30% versus 57%, P = 0.03). In multivariate analysis controlling for steroid use and diagnosis, age (odds ratio [OR] 1.37 per decade), coma grade (OR 2.02 grade 2, 2.65 grade 3, 5.29 grade 4), MELD (OR 1.07), and pH < 7.4 (OR 3.09) were significantly associated with mortality. Although steroid use was associated with a marginal benefit in SS overall (35% versus 23%, P = 0.047), this benefit did not persistent in multivariate analysis; mechanical ventilation (OR 0.24), MELD (OR 0.93), and alanine aminotransferase (1.02) were the only significant predictors of SS. CONCLUSION: Corticosteroids did not improve overall survival or SS in drug-induced, indeterminate, or autoimmune ALF and were associated with lower survival in patients with the highest MELD scores.

Postpartum care for mothers diagnosed with hepatitis B during pregnancy.

OBJECTIVE: We sought to determine rates of maternal postpartum hepatitis B virus (HBV) follow-up with a HBV specialist and identify factors associated with poor follow-up, as prior research has focused on infant outcomes and not maternal care. STUDY DESIGN: We conducted a retrospective review of data from Partners HealthCare system, the largest health care system in Massachusetts, and identified women with chronic HBV who delivered from 2002 through 2012. RESULTS: We identified 291 women (mean age 31.5 years, 51% Asian) with incident HBV during pregnancy. In all, 47% had postpartum follow-up with a HBV specialist, but only 19% also had appropriate laboratory tests (hepatitis B e antigen [HBeAg], hepatitis B e antibody, HBV DNA, and ALT) within 1 year of their HBV diagnosis. Mothers with HBV follow-up were more likely to have a primary care physician (PCP) within the Partners HealthCare system (66% vs 38%, P < .0001), a positive HBeAg (20% vs 8%, P = .004), and elevated AST values (17% vs 8%, P = .02). On multivariable logistic regression analysis, a mother who had a PCP (odds ratio, 2.50; 95% confidence interval, 1.37-4.59) or positive HBeAg (odds ratio, 4.45; 95% confidence interval, 1.64-12.06) had a greater likelihood of having HBV follow-up. CONCLUSION: Only 19% of HBV-infected mothers met care guidelines 1 year after being diagnosed with HBV. Inadequate postpartum HBV care affects women of all races/ethnicities. Women who had a PCP as well as those who were HBeAg positive were more likely to be referred for postpartum follow-up with a HBV specialist, suggesting that providers might be referring patients when they perceive HBV to be more serious or complex.

Multicenter review of liver transplant for hepatitis B-related liver disease: disparities in gender and ethnicity.

Orthotopic liver transplantation (OLT) is the preferred treatment for selected patients with hepatitis B virus (HBV)-related liver disease. This study aimed to (i) define long-term outcomes following OLT for HBV; (ii) to quantify the incidence of HBV recurrence (rHBV) as it relates to anti-HBV treatment; and (iii) to determine outcomes for specific patient subgroups. We performed a retrospective chart review of 738 patients undergoing OLT between 1985 and 2010 at seven US transplant centers and divided the patients into 3 eras, 1985-1994, 1995-2004, and 2005-2010, based on hepatitis B immunoglobulin and antiviral therapies. In Era 3, female gender (p = 0.002), recurrent hepatocellular cancer (p < 0.001), and retransplantation (p = 0.01) were significantly associated with worse survival on multivariate analysis. Survival at three yr was poor for all ethnicities in Era 1, but significantly improved for all except black Americans by Era 3. Era 2 data showed a continued increase in rHBV from five to 10 yr (16.6%, 26.2%). In conclusion, while OLT outcomes have improved because of combination antiviral and immunoglobulin therapy, women and black Americans may not have realized an equal benefit. The rate of rHBV is significant even 10 yr post-transplant with survival affected.

Prevention of de novo hepatitis B with adefovir dipivoxil in recipients of liver grafts from hepatitis B core antibody-positive donors.

Lamivudine has been shown to prevent de novo hepatitis B virus (HBV) infections in liver transplantation (LT) patients receiving hepatitis B core antibody-positive (HBcAb(+)) grafts, but it may produce long-term resistance. Adefovir dipivoxil (ADV) might be effective in preventing de novo hepatitis and resistance. A single-center, prospective trial was conducted with 16 adults (10 men and 6 women, mean age = 54 ± 11 years) who underwent LT with HBcAb(+) grafts between September 2007 and October 2009. After LT, patients were given ADV [10 mg daily (adjusted for renal function)]. No hepatitis B immune globulin was administered. At LT, all graft recipients were hepatitis B surface antigen-negative (HBsAg(-)), 38% were surface antibody-positive (HBsAb(+)), and 50% were HBcAb(+). The median follow-up after LT was 1.8 years (range = 1.0-2.6 years). All recipients had undetectable HBV DNA (<40 IU/mL) after LT until the end of follow-up. One recipient (6%) who was HBsAb(-) and HBcAb(-) before LT became HBsAg(+) after 52 weeks. One recipient was switched from ADV to entecavir for chronic renal insufficiency, and 19% of the patients had renal dose adjustments. There was a nonsignificant trend of increasing creatinine levels over time (1.2 mg/dL at LT, 1.3 mg/dL 1 year after LT, and 2.0 mg/dL 2 years after LT, P = 0.27). A comparison with a control cohort of LT recipients with hepatitis C virus who did not receive ADV showed no difference in the creatinine levels at LT or 1 year after LT. In conclusion, ADV prophylaxis prevents HBV replication in recipients of HBcAb(+) livers but does not fully protect recipients from de novo HBV. Long-term follow-up is needed to better determine the risk of de novo infection.

Diagnosing celiac disease by video capsule endoscopy (VCE) when esophagogastroduodenoscopy (EGD) and biopsy is unable to provide a diagnosis: a case series.

BACKGROUND: Video capsule endoscopy (VCE) is mainly used to evaluate patients with celiac disease in whom their course after diagnosis has been unfavorable and the diagnosis of adenocarcinoma, lymphoma or refractory celiac disease is entertained, but it has been suggested that VCE could replace esophagogastroduodenoscopy (EGD) and biopsy under certain circumstances. METHODS: We report a single center case series of 8 patients with suspected celiac disease who were diagnosed by VCE. RESULTS: EGD and biopsy had been performed in 4 patients resulting in a negative biopsy, declined by 2, and contraindicated in 2 due to hemophilia and von Willebrand disease. In all patients, mucosal changes of scalloping, mucosal mosaicism and reduced folds were seen in either the duodenum or jejunum on VCE. Follow-up in 7 patients demonstrated improvement in either their serological abnormalities or their presenting clinical features on a gluten-free diet. CONCLUSIONS: Our case series demonstrates that VCE and the visualization of the characteristic mucosal changes of villous atrophy may replace biopsy as the mode of diagnosis when EGD is either declined or contraindicated, or when duodenal biopsies are negative and there remains a high index of suspicion. Further study is needed to clarify the role and cost of diagnosing celiac disease with VCE.

Double-blind randomized controlled trial of rifaximin for persistent symptoms in patients with celiac disease.

BACKGROUND: Small intestinal bacterial overgrowth (SIBO) is one cause of a poor response to a gluten-free diet (GFD) and persistent symptoms in celiac disease. Rifaximin has been reported to improve symptoms in non-controlled trials. AIMS: To determine the effect of rifaximin on gastrointestinal symptoms and lactulose-hydrogen breath tests in patients with poorly responsive celiac disease. METHODS: A single-center, double-blind, randomized, controlled trial of patients with biopsy-proven celiac disease and persistent gastrointestinal symptoms despite a GFD was conducted. Patients were randomized to placebo (n = 25) or rifaximin (n = 25) 1,200 mg daily for 10 days. They completed the Gastrointestinal Symptom Rating Scale (GSRS) and underwent lactulose-hydrogen breath tests at weeks 0, 2, and 12. An abnormal breath test was defined as: (1) a rise in hydrogen of ≥20 parts per million (ppm) within 100 min, or (2) two peaks ≥20 ppm over baseline. RESULTS: GSRS scores were unaffected by treatment with rifaximin, regardless of baseline breath tests. In a multivariable regression model, the duration of patients' gastrointestinal symptoms significantly predicted their overall GSRS scores (estimate 0.029, p < 0.006). According to criteria 1 and 2, respectively, SIBO was present in 55 and 8% of patients at baseline, intermittently present in 28 and 20% given placebo, and 28 and 12% given rifaximin. There was no difference in the prevalence of SIBO between placebo and treatment groups at weeks 2 and 12. CONCLUSIONS: Rifaximin does not improve patients' reporting of gastrointestinal symptoms and hydrogen breath tests do not reliably identify who will respond to antibiotic therapy.

Physician knowledge and appropriate utilization of computed tomographic colonography in colorectal cancer screening.

GOALS: To assess physician understanding of computed tomographic colonography (CTC) in colorectal cancer (CRC) screening guidelines in a pilot study. BACKGROUND: CTC is a sensitive and specific method of detecting colorectal polyps and cancer. However, several factors have limited its clinical availability, and CRC screening guidelines have issued conflicting recommendations. STUDY: A web-based survey was administered to physicians at two institutions with and without routine CTC availability. RESULTS: 398 of 1655 (24%) participants completed the survey, 59% was from the institution with routine CTC availability, 52% self-identified as trainees, and 15% as gastroenterologists. 78% had no personal experience with CTC. Only 12% was aware of any current CRC screening guidelines that included CTC. In a multiple regression model, gastroenterologists had greater odds of being aware of guidelines (OR 3.49, CI 1.67-7.26), as did physicians with prior CTC experience (OR 4.81, CI 2.39-9.68), controlling for institution, level of training, sex, and practice type. Based on guidelines that recommend CTC, when given a clinical scenario, 96% of physicians was unable to select the appropriate follow-up after a CTC, which was unaffected by institution. CONCLUSIONS: Most physicians have limited experience with CTC and are unaware of recent recommendations concerning CTC in CRC screening.

Epidemiology of hepatitis B and the role of vaccination.

Hepatitis B virus (HBV) is a major cause of morbidity and mortality with a disproportionate impact on Asia and Africa. Current guidelines recommend screening at-risk populations for chronic HBV infection so that diagnosed individuals can be linked to appropriate hepatitis care. The vast majority of infected individuals are undiagnosed and untreated, and are at risk of developing cirrhosis, liver failure, and hepatocellular carcinoma. In individuals who are not yet infected, the HBV vaccine is safe and highly effective at preventing disease transmission. Countries with successful vaccination programs have been able to dramatically reduce their HBV prevalence. A concerted effort to screen, treat, and vaccinate at-risk individuals has the potential to eliminate HBV as a public health threat by 2030.