Browsing by Author "Rockey, Don C."

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    Amoxicillin-Clavulanate-Induced Liver Injury
    (Springer, 2016-08) deLomos, Andrew S.; Ghabril, Marwan; Rockey, Don C.; Gu, Jiezhun; Barnhart, Huiman X.; Fontana, Robert J.; Kleiner, David E.; Bonkovsky, Herbert L.; Department of Medicine, IU School of Medicine
    Background and Aims Amoxicillin–clavulanate (AC) is the most frequent cause of idiosyncratic drug-induced injury (DILI) in the US DILI Network (DILIN) registry. Here, we examined a large cohort of AC-DILI cases and compared features of AC-DILI to those of other drugs. Methods Subjects with suspected DILI were enrolled prospectively, and cases were adjudicated as previously described. Clinical variables and outcomes of patients with AC-DILI were compared to the overall DILIN cohort and to DILI caused by other antimicrobials. Results One hundred and seventeen subjects with AC-DILI were identified from the cohort (n = 1038) representing 11 % of all cases and 24 % of those due to antimicrobial agents (n = 479). Those with AC-DILI were older (60 vs. 48 years, P < 0.001). AC-DILI was more frequent in men than women (62 vs. 39 %) compared to the overall cohort (40 vs. 60 %, P < 0.001). The mean time to symptom onset was 31 days. The Tb, ALT, and ALP were 7 mg/dL, 478, and 325 U/L at onset. Nearly all liver biopsies showed prominent cholestatic features. Resolution of AC-DILI, defined by return of Tb to <2.5 mg/dL, occurred on average 55 days after the peak value. Three female subjects required liver transplantation, and none died due to DILI. Conclusion AC-DILI causes a moderately severe, mixed hepatocellular–cholestatic injury, particularly in older men, unlike DILI in general, which predominates in women. Although often protracted, eventual apparent recovery is typical, particularly for men and usually in women, but three women required liver transplantation.
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    Consensus Guidelines: Best Practices for Detection, Assessment and Management of Suspected Acute Drug-Induced Liver Injury During Clinical Trials in Adults with Chronic Viral Hepatitis and Adults with Cirrhosis Secondary to Hepatitis B, C and Nonalcoholic Steatohepatitis
    (Springer, 2021) Treem, William R.; Palmer, Melissa; Lonjon‑Domanec, Isabelle; Seekins, Daniel; Dimick‑Santos, Lara; Avigan, Mark I.; Marcinak, John F.; Dash, Ajit; Regev, Arie; Maller, Eric; Patwardhan, Meenal; Lewis, James H.; Rockey, Don C.; Di Bisceglie, Adrian M.; Freston, James W.; Andrade, Raul J.; Chalasani, Naga; Medicine, School of Medicine
    With the widespread development of new drugs to treat chronic liver diseases (CLDs), including viral hepatitis and nonalcoholic steatohepatitis (NASH), more patients are entering trials with abnormal baseline liver tests and with advanced liver injury, including cirrhosis. The current regulatory guidelines addressing the monitoring, diagnosis, and management of suspected drug-induced liver injury (DILI) during clinical trials primarily address individuals entering with normal baseline liver tests. Using the same laboratory criteria cited as signals of potential DILI in studies involving patients with no underlying liver disease and normal baseline liver tests may result in premature and unnecessary cessation of a study drug in a clinical trial population whose abnormal and fluctuating liver tests are actually due to their underlying CLD. This position paper focuses on defining best practices for the detection, monitoring, diagnosis, and management of suspected acute DILI during clinical trials in patients with CLD, including hepatitis C virus (HCV) and hepatitis B virus (HBV), both with and without cirrhosis and NASH with cirrhosis. This is one of several position papers developed by the IQ DILI Initiative, comprising members from 16 pharmaceutical companies in collaboration with DILI experts from academia and regulatory agencies. It is based on an extensive literature review and discussions between industry members and experts from outside industry to achieve consensus regarding the recommendations. Key conclusions and recommendations include (1) the importance of establishing laboratory criteria that signal potential DILI events and that fit the disease indication being studied in the clinical trial based on knowledge of the natural history of test fluctuations in that disease; (2) establishing a pretreatment value that is based on more than one screening determination, and revising that baseline during the trial if a new nadir is achieved during treatment; (3) basing rules for increased monitoring and for stopping drug for potential DILI on multiples of baseline liver test values and/or a threshold value rather than multiples of the upper limit of normal (ULN) for that test; (4) making use of more sensitive tests of liver function, including direct bilirubin (DB) or combined parameters such as aspartate transaminase:alanine transaminase (AST:ALT) ratio or model for end-stage liver disease (MELD) to signal potential DILI, especially in studies of patients with cirrhosis; and (5) being aware of potential confounders related to complications of the disease being studied that may masquerade as DILI events.
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    Current Knowledge and Research Priorities in the Digestive Manifestations of COVID-19
    (Elsevier, 2020) Aroniadis, Olga C.; DiMaio, Christopher J.; Dixon, Rebekah E.; Elmunzer, B. Joseph; Kolb, Jennifer M.; Mendelsohn, Robin; Ordiah, Collins O.; Rockey, Don C.; Singal, Amit G.; Spitzer, Rebecca L.; Tierney, William M.; Wani, Sachin; Yadav, Dhiraj; Global Health, School of Public Health
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    Digestive Manifestations in Patients Hospitalized With Coronavirus Disease 2019
    (Elsevier, 2020-10-01) Elmunzer, B. Joseph; Spitzer, Rebecca L.; Foster, Lydia D.; Merchant, Ambreen A.; Howard, Eric F.; Patel, Vaishali A.; West, Mary K.; Qayed, Emad; Nustas, Rosemary; Zakaria, Ali; Piper, Marc S.; Taylor, Jason R.; Jaza, Lujain; Forbes, Nauzer; Chau, Millie; Lara, Luis F.; Papachristou, Georgios I.; Volk, Michael L.; Hilson, Liam G.; Zhou, Selena; Kushnir, Vladimir M.; Lenyo, Alexandria M.; McLeod, Caroline G.; Amin, Sunil; Kuftinec, Gabriela N.; Yadav, Dhiraj; Fox, Charlie; Kolb, Jennifer M.; Pawa, Swati; Pawa, Rishi; Canakis, Andrew; Huang, Christopher; Jamil, Laith H.; Aneese, Andrew M.; Glamour, Benita K.; Smith, Zachary L.; Hanley, Katherine A.; Wood, Jordan; Patel, Harsh K.; Shah, Janak N.; Agarunov, Emil; Sethi, Amrita; Fogel, Evan L.; McNulty, Gail; Haseeb, Abdul; Trieu, Judy A.; Dixon, Rebekah E.; Yang, Jeong Yun; Mendelsohn, Robin B.; Calo, Delia; Aroniadis, Olga C.; LaComb, Joseph F.; Scheiman, James M.; Sauer, Bryan G.; Dang, Duyen T.; Piraka, Cyrus R.; Shah, Eric D.; Pohl, Heiko; Tierney, William M.; Mitchell, Stephanie; Condon, Ashwinee; Lenhart, Adrienne; Dua, Kulwinder S.; Kanagala, Vikram S.; Kamal, Ayesha; Singh, Vikesh K.; Pinto-Sanchez, Maria Ines; Hutchinson, Joy M.; Kwon, Richard S.; Korsnes, Sheryl J.; Singh, Harminder; Solati, Zahra; Willingham, Field F.; Yachimski, Patrick S.; Conwell, Darwin L.; Mosier, Evan; Azab, Mohamed; Patel, Anish; Buxbaum, James; Wani, Sachin; Chak, Amitabh; Hosmer, Amy E.; Keswani, Rajesh N.; DiMaio, Christopher J.; Bronze, Michael S.; Muthusamy, Raman; Canto, Marcia I.; Gjeorgjievski, V. Mihajlo; Imam, Zaid; Odish, Fadi; Edhi, Ahmed I.; Orosey, Molly; Tiwari, Abhinav; Patwardhan, Soumil; Brown, Nicholas G.; Patel, Anish A.; Ordiah, Collins O.; Sloan, Ian P.; Cruz, Lilian; Koza, Casey L.; Okafor, Uchechi; Hollander, Thomas; Furey, Nancy; Reykhart, Olga; Zbib, Natalia H.; Damianos, John A.; Esteban, James; Hajidiacos, Nick; Saul, Melissa; Mays, Melanie; Anderson, Gulsum; Wood, Kelley; Mathews, Laura; Diakova, Galina; Caisse, Molly; Wakefield, Lauren; Nitchie, Haley; Waljee, Akbar K.; Tang, Weijing; Zhang, Yueyang; Zhu, Ji; Deshpande, Amar R.; Rockey, Don C.; Alford, Teldon B.; Durkalski, Valerie; Medicine, School of Medicine
    Background & Aims The prevalence and significance of digestive manifestations in coronavirus disease 2019 (COVID-19) remain uncertain. We aimed to assess the prevalence, spectrum, severity, and significance of digestive manifestations in patients hospitalized with COVID-19. Methods Consecutive patients hospitalized with COVID-19 were identified across a geographically diverse alliance of medical centers in North America. Data pertaining to baseline characteristics, symptomatology, laboratory assessment, imaging, and endoscopic findings from the time of symptom onset until discharge or death were abstracted manually from electronic health records to characterize the prevalence, spectrum, and severity of digestive manifestations. Regression analyses were performed to evaluate the association between digestive manifestations and severe outcomes related to COVID-19. Results A total of 1992 patients across 36 centers met eligibility criteria and were included. Overall, 53% of patients experienced at least 1 gastrointestinal symptom at any time during their illness, most commonly diarrhea (34%), nausea (27%), vomiting (16%), and abdominal pain (11%). In 74% of cases, gastrointestinal symptoms were judged to be mild. In total, 35% of patients developed an abnormal alanine aminotransferase or total bilirubin level; these were increased to less than 5 times the upper limit of normal in 77% of cases. After adjusting for potential confounders, the presence of gastrointestinal symptoms at any time (odds ratio, 0.93; 95% CI, 0.76–1.15) or liver test abnormalities on admission (odds ratio, 1.31; 95% CI, 0.80–2.12) were not associated independently with mechanical ventilation or death. Conclusions Among patients hospitalized with COVID-19, gastrointestinal symptoms and liver test abnormalities were common, but the majority were mild and their presence was not associated with a more severe clinical course.
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    Digestive Manifestations in Patients Hospitalized With Coronavirus Disease 2019
    (Elsevier, 2021-07) Elmunzer, B. Joseph; Spitzer, Rebecca L.; Foster, Lydia D.; Merchant, Ambreen A.; Howard, Eric F.; Patel, Vaishali A.; West, Mary K.; Qayed, Emad; Nustas, Rosemary; Zakaria, Ali; Piper, Marc S.; Taylor, Jason R.; Jaza, Lujain; Forbes, Nauzer; Chau, Millie; Lara, Luis F.; Papachristou, Georgios I.; Volk, Michael L.; Hilson, Liam G.; Zhou, Selena; Kushnir, Vladimir M.; Lenyo, Alexandria M.; McLeod, Caroline G.; Amin, Sunil; Kuftinec, Gabriela N.; Yadav, Dhiraj; Fox, Charlie; Kolb, Jennifer M.; Pawa, Swati; Pawa, Rishi; Canakis, Andrew; Huang, Christopher; Jamil, Laith H.; Aneese, Andrew M.; Glamour, Benita K.; Smith, Zachary L.; Hanley, Katherine A.; Wood, Jordan; Patel, Harsh K.; Shah, Janak N.; Agarunov, Emil; Sethi, Amrita; Fogel, Evan L.; McNulty, Gail; Haseeb, Abdul; Trieu, Judy A.; Dixon, Rebekah E.; Yang, Jeong Yun; Mendelsohn, Robin B.; Calo, Delia; Aroniadis, Olga C.; LaComb, Joseph F.; Scheiman, James M.; Sauer, Bryan G.; Dang, Duyen T.; Piraka, Cyrus R.; Shah, Eric D.; Pohl, Heiko; Tierney, William M.; Mitchell, Stephanie; Condon, Ashwinee; Lenhart, Adrienne; Dua, Kulwinder S.; Kanagala, Vikram S.; Kamal, Ayesha; Singh, Vikesh K.; Pinto-Sanchez, Maria Ines; Hutchinson, Joy M.; Kwon, Richard S.; Korsnes, Sheryl J.; Singh, Harminder; Solati, Zahra; Willingham, Field F.; Yachimski, Patrick S.; Conwell, Darwin L.; Mosier, Evan; Azab, Mohamed; Patel, Anish; Buxbaum, James; Wani, Sachin; Chak, Amitabh; Hosmer, Amy E.; Keswani, Rajesh N.; DiMaio, Christopher J.; Bronze, Michael S.; Muthusamy, Raman; Canto, Marcia I.; Gjeorgjievski, V. Mihajlo; Imam, Zaid; Odish, Fadi; Edhi, Ahmed I.; Orosey, Molly; Tiwari, Abhinav; Patwardhan, Soumil; Brown, Nicholas G.; Patel, Anish A.; Ordiah, Collins O.; Sloan, Ian P.; Cruz, Lilian; Koza, Casey L.; Okafor, Uchechi; Hollander, Thomas; Furey, Nancy; Reykhart, Olga; Zbib, Natalia H.; Damianos, John A.; Esteban, James; Hajidiacos, Nick; Saul, Melissa; Mays, Melanie; Anderson, Gulsum; Wood, Kelley; Mathews, Laura; Diakova, Galina; Caisse, Molly; Wakefield, Lauren; Nitchie, Haley; Waljee, Akbar K.; Tang, Weijing; Zhang, Yueyang; Zhu, Ji; Deshpande, Amar R.; Rockey, Don C.; Alford, Teldon B.; Durkalski, Valerie; North American Alliance for the Study of Digestive Manifestations of COVID-19; Medicine, School of Medicine
    BACKGROUND & AIMS: The prevalence and significance of digestive manifestations in coronavirus disease 2019 (COVID-19) remain uncertain. We aimed to assess the prevalence, spectrum, severity, and significance of digestive manifestations in patients hospitalized with COVID-19. METHODS: Consecutive patients hospitalized with COVID-19 were identified across a geographically diverse alliance of medical centers in North America. Data pertaining to baseline characteristics, symptomatology, laboratory assessment, imaging, and endoscopic findings from the time of symptom onset until discharge or death were abstracted manually from electronic health records to characterize the prevalence, spectrum, and severity of digestive manifestations. Regression analyses were performed to evaluate the association between digestive manifestations and severe outcomes related to COVID-19. RESULTS: A total of 1992 patients across 36 centers met eligibility criteria and were included. Overall, 53% of patients experienced at least 1 gastrointestinal symptom at any time during their illness, most commonly diarrhea (34%), nausea (27%), vomiting (16%), and abdominal pain (11%). In 74% of cases, gastrointestinal symptoms were judged to be mild. In total, 35% of patients developed an abnormal alanine aminotransferase or total bilirubin level; these were increased to less than 5 times the upper limit of normal in 77% of cases. After adjusting for potential confounders, the presence of gastrointestinal symptoms at any time (odds ratio, 0.93; 95% CI, 0.76-1.15) or liver test abnormalities on admission (odds ratio, 1.31; 95% CI, 0.80-2.12) were not associated independently with mechanical ventilation or death. CONCLUSIONS: Among patients hospitalized with COVID-19, gastrointestinal symptoms and liver test abnormalities were common, but the majority were mild and their presence was not associated with a more severe clinical course.
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    Garcinia cambogia, Either Alone or in Combination With Green Tea, Causes Moderate to Severe Liver Injury
    (Elsevier, 2021) Vuppalanchi, Raj; Bonkovsky, Herbert L.; Ahmad, Jawad; Barnhart, Huiman; Durazo, Francisco; Fontana, Robert J.; Gu, Jiezhun; Khan, Ikhlas; Kleiner, David E.; Koh, Christopher; Rockey, Don C.; Phillips, Elizabeth J.; Li, Yi-Ju; Serrano, Jose; Stolz, Andrew; Tillmann, Hans L.; Seeff, Leonard B.; Hoofnagle, Jay H.; Navarro, Victor J.; Medicine, School of Medicine
    Background & Aims Garcinia cambogia, either alone or with green tea, is commonly promoted for weight loss. Sporadic cases of liver failure from G cambogia have been reported, but its role in liver injury is controversial. Methods Among 1418 patients enrolled in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2018, we identified 22 cases (adjudicated with high confidence) of liver injury from G cambogia either alone (n = 5) or in combination with green tea (n = 16) or Ashwagandha (n = 1). Control groups consisted of 57 patients with liver injury from herbal and dietary supplements (HDS) containing green tea without G cambogia and 103 patients from other HDS. Results Patients who took G cambogia were between 17 and 54 years, with liver injury arising 13–223 days (median = 51) after the start. One patient died, one required liver transplantation, and 91% were hospitalized. The liver injury was hepatocellular with jaundice. Although the peak values of aminotransferases were significantly higher (2001 ± 1386 U/L) in G cambogia group (P < .018), the median time for improvement in total bilirubin was significantly lower compared with the control groups (10 vs 17 and 13 days; P = .03). The presence of HLA-B∗35:01 allele was significantly higher in the G cambogia containing HDS (55%) compared with patients because of other HDS (19%) (P = .002) and those with acute liver injury from conventional drugs (12%) (P = 2.55 × 10–6). Conclusions The liver injury caused by G cambogia and green tea is clinically indistinguishable. The possible association with HLA-B∗35:01 allele suggests an immune-mediated mechanism of injury. Clinical Trials.gov number: NCT00345930.
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    HLA-B*35:01 and Green Tea Induced Liver Injury
    (Wiley, 2021-06) Hoofnagle, Jay H.; Bonkovsky, Herbert L.; Phillips, Elizabeth J.; Li, Yi-Ju; Ahmad, Jawad; Barnhart, Huiman; Durazo, Francisco; Fontana, Robert J.; Gu, Jiezhun; Khan, Ikhlas; Kleiner, David E.; Koh, Christopher; Rockey, Don C.; Seeff, Leonard B.; Serrano, Jose; Stolz, Andrew; Tillmann, Hans L.; Vuppalanchi, Raj; Navarro, Victor J.; Medicine, School of Medicine
    Background and aims: Herbal supplements, and particularly multi-ingredient products, have become increasingly common causes of acute liver injury. Green tea is a frequent component in implicated products, but its role in liver injury is controversial. The aim of this study was to better characterize the clinical features, outcomes, and pathogenesis of green tea-associated liver injury. Approach and results: Among 1,414 patients enrolled in the U.S. Drug-Induced Liver Injury Network who underwent formal causality assessment, 40 cases (3%) were attributed to green tea, 202 to dietary supplements without green tea, and 1,142 to conventional drugs. The clinical features of green tea cases and representation of human leukocyte antigen (HLA) class I and II alleles in cases and control were analyzed in detail. Patients with green tea-associated liver injury ranged in age from 17 to 69 years (median = 40) and developed symptoms 15-448 days (median = 72) after starting the implicated agent. The liver injury was typically hepatocellular (95%) with marked serum aminotransferase elevations and only modest increases in alkaline phosphatase. Most patients were jaundiced (83%) and symptomatic (88%). The course was judged as severe in 14 patients (35%), necessitating liver transplantation in 3 (8%), but rarely resulting in chronic injury (3%). In three instances, injury recurred upon re-exposure to green tea with similar clinical features, but shorter time to onset. HLA typing revealed a high prevalence of HLA-B*35:01, found in 72% (95% confidence interval [CI], 58-87) of green tea cases, but only 15% (95% CI, 10-20) caused by other supplements and 12% (95% CI, 10-14) attributed to drugs, the latter rate being similar to population controls (11%; 95% CI, 10.5-11.5). Conclusions: Green tea-related liver injury has distinctive clinical features and close association with HLA-B*35:01, suggesting that it is idiosyncratic and immune mediated.
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    Prioritization of Therapeutic Targets and Trial Design in Cirrhotic Portal Hypertension
    (Wiley, 2019-03) Abraldes, Juan G.; Trebicka, Jonel; Chalasani, Naga; D’Amico, Gennaro; Rockey, Don C.; Shah, Vijay H.; Bosch, Jaime; Garcia-Tsao, Guadalupe; Medicine, School of Medicine
    Portal hypertension (PH) is the main driver of cirrhosis decompensation, the main determinant of death in patients with cirrhosis. PH results initially from increased intrahepatic vascular resistance. Subsequently, increased inflow from splanchnic vasodilation and increased cardiac output lead to a further increase in portal pressure (PP). Reducing PP in cirrhosis results in better outcomes. Removing the cause of cirrhosis might improve PP. However, this is a slow process and patients may continue to be at risk of decompensation. Additionally, for some chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD), etiological treatments are not yet available. Therefore, there is a need to develop better therapies specifically aimed at reducing PP. For over 35 years, the mainstay of such therapy has been the use of nonselective beta‐blockers (NSBBs) that act by reducing portal venous inflow. Recently, many drugs (mainly targeting intrahepatic mechanisms) have shown promise in preclinical and early clinical studies and may act alone or synergistically with NSBBs in reducing PP in cirrhosis. The objective of this position paper is to propose a novel framework for the design of clinical trials (phase 1, 2, and 3) in patients with cirrhosis and PH and to prioritize targets and pharmacological therapies in this setting. We have focused the discussion on patients with compensated cirrhosis. The paper summarizes discussions held at The American Association for the Study of Liver Diseases (AASLD) Industry Colloquium in January 2018, with the participation of clinical and translational investigators, regulatory professionals, and industry partners.
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    Reliability of causality assessment for drug, herbal and dietary supplement hepatotoxicity in the Drug-Induced Liver Injury Network (DILIN)
    (Wiley, 2015-05) Hayashi, Paul H.; Barnhart, Huiman X.; Fontana, Robert J.; Chalasani, Naga; Davern, Timothy J.; Talwalkar, Jayant A.; Reddy, K. Rajender; Stolz, Andrew A.; Hoofnagle, Jay H.; Rockey, Don C.; Department of Medicine, IU School of Medicine
    BACKGROUND & AIMS: Because of the lack of objective tests to diagnose drug-induced liver injury (DILI), causality assessment is a matter of debate. Expert opinion is often used in research and industry, but its test-retest reliability is unknown. To determine the test-retest reliability of the expert opinion process used by the Drug-Induced Liver Injury Network (DILIN). METHODS: Three DILIN hepatologists adjudicate suspected hepatotoxicity cases to one of five categories representing levels of likelihood of DILI. Adjudication is based on retrospective assessment of gathered case data that include prospective follow-up information. One hundred randomly selected DILIN cases were re-assessed using the same processes for initial assessment but by three different reviewers in 92% of cases. RESULTS: The median time between assessments was 938 days (range 140-2352). Thirty-one cases involved >1 agent. Weighted kappa statistics for overall case and individual agent category agreement were 0.60 (95% CI: 0.50-0.71) and 0.60 (0.52-0.68) respectively. Overall case adjudications were within one category of each other 93% of the time, while 5% differed by two categories and 2% differed by three categories. Fourteen per cent crossed the 50% threshold of likelihood owing to competing diagnoses or atypical timing between drug exposure and injury. CONCLUSIONS: The DILIN expert opinion causality assessment method has moderate interobserver reliability but very good agreement within one category. A small but important proportion of cases could not be reliably diagnosed as ≥50% likely to be DILI.
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    U.S. Physician-Scientist Workforce in the 21st Century: Recommendations to Attract and Sustain the Pipeline
    (Wolters Kluwer, 2018-04) Salata, Robert A.; Geraci, Mark W.; Rockey, Don C.; Blanchard, Melvin; Brown, Nancy J.; Cardinal, Lucien J.; Garcia, Maria; Madaio, Michael P.; Marsh, James D.; Todd, Robert F.; Medicine, School of Medicine
    The U.S. physician-scientist (PS) workforce is invaluable to the nation's biomedical research effort. It is through biomedical research that certain diseases have been eliminated, cures for others have been discovered, and medical procedures and therapies that save lives have been developed. Yet, the U.S. PS workforce has both declined and aged over the last several years. The resulting decreased inflow and outflow to the PS pipeline renders the system vulnerable to collapsing suddenly as the senior workforce retires. In November 2015, the Alliance for Academic Internal Medicine hosted a consensus conference on the PS workforce to address issues impacting academic medical schools, with input from early-career PSs based on their individual experiences and concerns. One of the goals of the conference was to identify current impediments in attracting and supporting PSs and to develop a new set of recommendations for sustaining the PS workforce in 2016 and beyond. This Perspective reports on the opportunities and factors identified at the conference and presents five recommendations designed to increase entry into the PS pipeline and nine recommendations designed to decrease attrition from the PS workflow.