Physician Scientist Training in the United States: A Survey of the Current Literature.

The declining number of physician scientists is an alarming issue. A systematic review of all existing programs described in the literature was performed, so as to highlight which programs may serve as the best models for the training of successful physician scientists. Multiple databases were searched, and 1,294 articles related to physician scientist training were identified. Preference was given to studies that looked at number of confirmed publications and/or research grants as primary outcomes. Thirteen programs were identified in nine studies. Eighty-three percent of Medical Scientist Training Program (MSTP) graduates, 77% of Clinician Investigator Training Program (CI) graduates, and only 16% of Medical Fellows Program graduates entered a career in academics. Seventy-eight percent of MSTP graduates succeeded in obtaining National Institute of Health (NIH) grants, while only 15% of Mayo Clinic National Research Service Award-T32 graduates obtained NIH grants. MSTP physician scientists who graduated in 1990 had 13.5 ± 12.5 publications, while MSTP physician scientists who graduated in 1975 had 51.2 ± 38.3 publications. Additionally, graduates from the Mayo Clinic's MD-PhD Program, the CI Program, and the NSRA Program had 18.2 ± 20.1, 26.5 ± 24.5, and 17.9 ± 26.3 publications, respectively. MSTP is a successful model for the training of physician scientists in the United States, but training at the postgraduate level also shows promising outcomes. An increase in the number of positions available for training at the postgraduate level should be considered.

Short-term use of glucocorticoids and risk of peptic ulcer bleeding: a nationwide population-based case-crossover study.

BACKGROUND: Controversy exists regarding glucocorticoids therapy and the risk of peptic ulcer bleeding (PUB). AIM: The present study was undertaken to determine whether short-term use of glucocorticoids is associated with the occurrence of peptic ulcer bleeding. METHODS: The records of adult patients hospitalised for newly diagnosed peptic ulcer bleeding from 2000 to 2012 were retrieved from the Taiwan National Health Insurance Research Database, a nationwide population-based registry system. The association between systemic glucocorticoids usage and peptic ulcer bleeding was determined with a conditional logistic regression model comparing cases and controls during time windows of 7, 14 and 28 days using a case-crossover design. RESULTS: Of the 8894 enrolled patients, the adjusted self-matched odds ratios for peptic ulcer bleeding after exposure to the glucocorticoids were 1.37 (95% CI: 1.12-1.68, P = 0.003) for the 7-day window, 1.66 (95% CI: 1.38-2.00, P < 0.001) for the 14-day window and 1.84 (95% CI: 1.57-2.16, P < 0.001) for the 28-day window. Moderate to high, but not low dose glucocorticoids (methylprednisolone <4 mg/day or its equivalence) were associated with an increased risk of peptic ulcer bleeding. Concomitant use of a nonselective nonsteroidal anti-inflammatory drug (NSAID) or aspirin further elevated the risk. However, it does not eliminate the effect of underlying diseases flare-up that may have placed the patients at risk for peptic ulcer bleeding in this kind of study design. CONCLUSIONS: Short-term (7-28 days) exposure to glucocorticoids is significantly associated with peptic ulcer bleeding; this risk seems dose-dependent and is higher when nonselective NSAIDs or aspirin are used concurrently.

Alendronate, a bisphosphonate, increased upper and lower gastrointestinal bleeding: risk factor analysis from a nationwide population-based study.

UNLABELLED: Patients receiving alendronate for osteoporosis carry a significantly higher risk of developing upper gastrointestinal bleeding (GIB) and lower GIB (hazard ratio 1.32 and 1.84, respectively) after adjusting for potential confounding factors such as age, gender, co-morbidity, and some medications. The risk factors associated with GIB were further analyzed. INTRODUCTION: Patients receiving alendronate, a type of bisphosphonate, for osteoporosis have a higher risk of developing upper gastrointestinal bleeding (UGIB). Whether patients receiving alendronate also have a higher risk of lower gastrointestinal bleeding (LGIB) has not been studied. In this study, we investigated the association between GIB and alendronate use and to identify the possible risk factors of GIB among alendronate users. METHODS: Using the National Health Insurance (NHI) Research Database of Taiwan, 3,000 alendronate users and 12,000 age-, sex-, and enrollment time-matched controls were extracted for analysis from a cohort data set of 1,000,000 randomly sampled subjects. Cox proportional hazard regression models were used to identify the risk factors for UGIB and LGIB in all enrollees and alendronate users after adjustments for age, gender, comorbidity (hypertension, diabetes mellitus, coronary heart disease, heart failure, chronic renal disease, chronic obstructive pulmonary disease, peptic ulcer, and cirrhosis), and medications (nonsteroidal anti-inflammatory drugs [NSAIDs], aspirin, steroids, clopidogrel, ticlopidine, warfarin, and selective serotonin reuptake inhibitors). RESULTS: During a median of 1.30-year follow-up, patients receiving alendronate had significant higher risk of UGIB and LGIB after adjusting for age, gender, and potential confounding factors such as comorbidity and medications. Age, chronic renal disease, NSAID, and clopidogrel use may be independent risk factors for UGIB among alendronate users. Age, male gender, clopidogrel, and ticlopidine use may be independent risk factors for LGIB among alendronate users. CONCLUSION: Patients receiving alendronates seemed to carry a higher risk for UGIB and LGIB, respectively, after adjustment for age, sex, underlying comorbidity, and certain medications.

Risk factors of gastrointestinal bleeding in clopidogrel users: a nationwide population-based study.

BACKGROUND: The risk factors for gastrointestinal bleeding (GIB) in clopidogrel users have not been identified. AIM: To clarify whether clopidogrel use is a risk factor for upper GIB (UGIB) and lower GIB (LGIB) and identify the risk factors in clopidogrel users. METHODS: Using the National Health Insurance Research Database of Taiwan, 3238 clopidogrel users and 12,952 age-, sex-, and enrolment time-matched controls in a 1:4 ratio were extracted for comparison from a cohort dataset of 1,000,000 randomly sampled subjects. Cox proportional hazard regression models were used to identify the independent risk factors for UGIB and LGIB in all enrollees and clopidogrel users after adjustments for age, gender, comorbidity [i.e., coronary artery disease, hypertension, diabetes, chronic obstructive pulmonary disease, chronic kidney disease (CKD), cirrhosis, uncomplicated peptic ulcer disease, and peptic ulcer bleeding (PUB)], and medications [e.g., nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 inhibitors, aspirin, steroids, selective serotonin reuptake inhibitors (SSRIs), warfarin and alendronate]. RESULTS: Cox proportional hazard regression analysis showed that use of clopidogrel increased the risk of UGIB [hazard ratio (HR): 3.66; 95% confidence interval (CI): 2.96-4.51] and LGIB [HR: 3.52, 95% CI: 2.74-4.52]. Age, CKD, PUB history, use of aspirin and NSAIDs were independent risk factors for UGIB in the clopidogrel users. Age, CKD, PUB history, use of aspirin and SSRIs were independent risk factors for LGIB. CONCLUSIONS: In clopidogrel users, age, CKD, PUB history, use of aspirin and NSAIDs are independent risk factors for UGIB; age, CKD, PUB history, use of aspirin and SSRIs are independent risk factors for LGIB.

Cirrhotic patients at increased risk of peptic ulcer bleeding: a nationwide population-based cohort study.

BACKGROUND: Few large population-based studies have compared the occurrence of peptic ulcer bleeding (PUB) in cirrhotic and noncirrhotic patients. AIMS: To investigate if cirrhotic patients have higher risk of PUB than the general population and to identify possible risk factors of PUB in cirrhotic patients. METHODS: Using the National Health Insurance Research Database, a nationwide population-based dataset in Taiwan and matching age, gender, comorbidities and ulcerogenic medication by propensity score, 4013 cirrhotic patients, 8013 chronic hepatitis patients and 7793 normal controls were compared. The log-rank test was used to analyse differences in accumulated PUB-free survival rates between the groups. Cox proportional hazard regressions were performed to evaluate independent risk factors for PUB in all patients and identified risk factors of PUB in cirrhotic patients. RESULTS: During the 7-year follow-up, cirrhotic patients had significantly higher incidences of PUB than chronic hepatitis patients and controls, respectively (P < 0.001 by log-rank test). By Cox proportional hazard regression analysis, cirrhosis was independently associated with increased risk of PUB (hazard ratio: 4.22; 95% CI 3.37-5.29, P < 0.001) after adjusting for age, gender, economic status, underlying comorbidities and ulcerogenic medication. Age, male, diabetes, chronic renal disease, history of gastro-oesophageal variceal bleeding and use of nonsteroidal anti-inflammatory drugs were risk factors for PUB in cirrhotic patients. CONCLUSION: Cirrhotic patients have a significantly higher risk of peptic ulcer bleeding after adjustments for possible confounding factors like age, gender, economic status, underlying comorbidities and ulcerogenic medication.

Cancer risk in patients with pyogenic liver abscess: a nationwide cohort study.

BACKGROUND: There has been no large-scale population-based study on the relationship between pyogenic liver abscesses (PLA) and subsequent cancer risk. AIM: To estimate all cancer risk following a diagnosis of PLA. METHODS: Based on Taiwan's National Health Insurance Research Database, 1257 patients with PLA without prior cancers in the period 1996-2008 were identified and followed-up. The standard incidence ratio (SIR) of each cancer was calculated as the number of observed cancer cases arising among the PLA patients divided by the expected case number of cancer cases according to the national cancer rates. RESULTS: Of the 1257 PLA patients identified, 598 (47.6%) had diabetes mellitus. After a median (±s.d.) follow-up of 3.33 ± 3.45 years, 186 were diagnosed with cancers, including 56 liver cancer, 22 biliary tract cancer and 40 colorectal cancer patients. Patients with PLA had a higher risk of all cancers (SIR, 3.83; 95% CI, 3.30-4.42), liver cancer (SIR, 7.87; 95% CI, 5.94-10.21), biliary tract cancer (SIR, 34.58; 95% CI, 21.67-52.36) and colorectal cancer (SIR, 5.27; 95% CI, 3.76-7.18). The highest SIRs of all cancers, liver cancer, biliary tract cancer and colorectal cancer occurred within 90 days of follow-up (360.82; 95% CI, 278.46-459.91, 257.28; 95% CI, 186.17-346.56, 1153.38; 95% CI 694.08-1801.24, and 52.63; 95% CI 25.2-96.8 respectively). CONCLUSIONS: Pyogenic liver abscesses may herald the onset of cancer, especially hepato-biliary and colon cancer. Further surveys should be conducted for the detection of occult cancers in such patients.

Randomised clinical trial: rabeprazole plus aspirin is not inferior to rabeprazole plus clopidogrel for the healing of aspirin-related peptic ulcer.

BACKGROUND: Clopidogrel does not inhibit prostaglandin synthesis. As a result, clopidogrel's incidence of peptic ulcer disease (PUD) and ulcer bleeding is lower than aspirin's. AIM: To compare the healing rate in aspirin-related dyspeptic ulcer patients who were given proton pump inhibitor (PPI) plus aspirin or PPI plus clopidogrel. METHODS: Patients with aspirin-related nonbleeding symptomatic ulcers were randomised to receive rabeprazole (20 mg/day) plus aspirin (100 mg/day) or rabeprazole (20 mg/day) plus clopidogrel (75 mg/day) for 12 weeks. The primary endpoint was the successful treatment of PUD as characterised by intention-to-treat at the end of therapy. RESULTS: Two hundred and eighteen patients (109 in the aspirin group and 109 in the clopidogrel group) were enrolled. There were no statistical demographic differences between the group that received aspirin and the group that received clopidogrel. The PUD treatment success rate was also statistically equal between the clopidogrel and aspirin groups (86.2% vs. 90.0%, P = 0.531). Neither group experienced ulcer-related bleeding. Multivariate logistic regression analysis showed that large ulcer size (>10 mm) (OR: 6.29, 95% CI: 2.58-15.37) and past history of PUD (OR: 3.69, 95% CI: 1.24-10.97) were important predictors of unsuccessful therapy for aspirin-related PUD. CONCLUSIONS: Rabeprazole plus aspirin is not inferior to rabeprazole plus clopidogrel in treating aspirin-related symptomatic PUD. Large ulcer size (>10 mm) and past history of PUD are important predictors of unsuccessful therapy (NCT 01037491).

Association of the G-protein and α2-adrenergic receptor gene and plasma norepinephrine level with clonidine improvement of the effects of diuretics in patients with cirrhosis with refractory ascites: a randomised clinical trial.

OBJECTIVE: Clonidine is an α(2)-adrenoceptor agonist which, by coupling with G-protein, has been proposed as an alternative treatment for refractory ascites of patients with cirrhosis for several years. Genetic polymorphisms of ß-adrenoceptor and angiotensin II type 1 receptor blockers have been reported to affect drug response in patients with cirrhosis. This study evaluated the clonidine-diuretic response rate, favourable predictors and genetic components of the clonidine-diuretic response in patients with cirrhosis with refractory ascites. METHODS: 270 patients with cirrhosis with refractory ascites were randomised equally into two treatment groups to receive diuretics alone or the clonidine-diuretics association. The primary end point was clonidine-diuretic response rate. Secondary end points were mean daily dose of diuretics, times of paracentesis, ascites-related readmission and 1-year survival rate. RESULTS: Good clonidine responders had better natriuresis and diuresis as well as a significant decrease in abdominal circumference, plasma renin, aldosterone and norepinephrine levels. The overall clonidine-diuretics response rate was 55-60%. In patients with cirrhosis, the prevalence of ARDA(2)C WD/DD and GNB3 CT/TT genotypes was 71% and 77%, respectively. Among the responders, 71% of patients with cirrhosis had the ARDA(2)C WD/DD genotype and 67% has the GNB3 CT/TT genotype. Besides higher baseline norepinephrine levels, the presence of both ARDA(2)C WD/DD and GNB3 CT/TT genotypes showed a positive predictive value of 82% and a negative predictive value of 79% for good clonidine response. CONCLUSIONS: These results suggest that neurohormonal and genetic testing may be used as predictive factors for the additive effects of clonidine on the diuresis and natriuresis effects of diuretics in patients with cirrhosis with refractory ascites.

Effects of endothelin-1 on portal-systemic collaterals of common bile duct-ligated cirrhotic rats.

BACKGROUND/AIMS: Endothelin-1 (ET-1) may induce intrahepatic vasoconstriction and consequently increase portal pressure. Endothelin-1 has been shown to exert a direct vasoconstrictive effect on the collateral vessels in partially portal vein-ligated rats with a high degree of portal-systemic shunting. This study investigated the collateral vascular responses to ET-1, the receptors in mediation and the regulation of ET-1 action by nitric oxide and prostaglandin in cirrhotic rats with a relatively low degree of portal-systemic shunting. METHODS: The portal-systemic collaterals of common bile duct-ligated (BDL) cirrhotic rats were tested by in situ perfusion. The concentration-response curves of collaterals to graded concentrations of ET-1 (10(-10)-10(-7) m) with or without BQ-123 (ET(A) receptor antagonist, 2 x 10(-6) m), BQ-788 (ET(B) receptor antagonist, 10(-7) m) or both were recorded. In addition, the collateral responses to ET-1 with preincubation of N(omega)-nitro-L-arginine (NNA, 10(-4) M), indomethacin (INDO, 10(-5) M) or in combination were assessed. RESULTS: Endothelin-1 significantly increased the perfusion pressures of portal-systemic collaterals. The ET-1-induced constrictive effects were inhibited by BQ-123 or BQ-123 plus BQ-788 but not by BQ-788 alone. The inhibitory effect was greater in the combination group. Pretreatment of NNA or NNA plus INDO equivalently enhanced the response of ET-1 while pretreatment of INDO alone exerted no effect. CONCLUSION: Endothelin-1 has a direct vasoconstrictive effect on the collaterals of BDL cirrhotic rats, mainly mediated by ET(A) receptor. Endogenous nitric oxide may play an important role in modulating the effects of ET-1 in the portal-systemic collaterals of BDL cirrhotic rats.

Cyclooxygenase expression in splanchnic hyposensitivity to glypressin of bleeding portal hypertensive rats.

BACKGROUND: Prostacyclin mediates, at least partly, the splanchnic vascular hyporesponsiveness to glypressin in bleeding portal hypertensive rats. This study investigated the relative contribution of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in the splanchnic hyposensitivity to glypressin in rats with portal hypertension induced by partial portal vein ligation (PVL). METHODS: Fourteen days after the operation, the rats were divided into without- and with-bleeding groups. Three series of PVL rats were used to investigate (i). the haemodynamic effects of glypressin (0.07 mg x kg(-1) intravenously), (ii). COX-1/COX-2 mRNA expression over abdominal aorta and superior mesenteric artery and (iii). plasma levels of 6-keto-prostaglandin-F1alpha. In rats with a hypotensive haemorrhage, 4.5 mL of blood was withdrawn and 50% of the withdrawn blood was re-infused before blood and vessel sampling or the administration of glypressin. RESULTS: Splanchnic hyposensitivity to glypressin was demonstrated in the haemorrhage-transfused PVL rats with enhanced COX-1 expression of superior mesenteric artery and increased plasma levels of 6-keto-prostaglandin-F1alpha. There were no differences in the COX-2 expression of superior mesenteric artery and COX-1 and COX-2 expressions of abdominal aorta between without- and with-bleeding groups. CONCLUSION: In portal hypertensive rats with acute haemorrhage, COX-1 over-expression in the superior mesenteric artery plays a role in mediating the splanchnic hyposensitivity to glypressin.

Hemodynamic effects of a combination of octreotide and terlipressin in patients with viral hepatitis related cirrhosis.

BACKGROUND: Terlipressin or octreotide given alone has been used as the first-line pharmacological treatment for acute variceal bleeding. In portal hypertensive animals, pre-infusion of octreotide followed by the addition of terlipressin has an additive or complementary effect on splanchnic hemodynamics. The current study was aimed at evaluating such a combination treatment in patients with cirrhosis and portal hypertension. METHODS: Patients were randomly assigned to receive either a placebo (n = 11) or an intravenous infusion of octreotide 100 microg/h after an initial bolus of 100 microg (n = 13). Thereafter, each patient received an intravenous injection of terlipressin 2 mg. Hemodynamic values were measured basally, 30 min after octreotide or placebo, and 60 min after terlipressin. RESULTS: Placebo administration did not affect any of the hemodynamic values. Terlipressin administration resulted in expected changes in hepatic venous pressure gradient, hepatic blood flow and systemic hemodynamics. In contrast, octreotide administration significantly decreased hepatic blood flow but did not affect other hemodynamic values. After terlipressin administration, significant hemodynamic changes were observed that were similar to the hemodynamic changes with terlipressin alone. The magnitude of changes in hepatic venous pressure gradient, cardiac index and systemic vascular resistance were no different between the two groups of patients. The heart rate was significantly lower in patients receiving octreotide plus terlipressin than those receiving terlipressin alone. CONCLUSION: The current study showed that a combination of octreotide and terlipressin did not exert an additive effect in reducing hepatic venous pressure gradient in patients with cirrhosis. In addition, the systemic hemodynamic changes were comparable between the two groups.

Bacteremia after endoscopic injection of N-butyl-2-cyanoacrylate for gastric variceal bleeding.

BACKGROUND: Cyanoacrylate may form a barrier that prevents bacterial invasion when used in tissue. Because cyanoacrylate polymerizes within seconds on contact with aqueous media, it is used worldwide to arrest gastric variceal bleeding. The aim of this study was to determine the frequency of bacteremia after endoscopic cyanoacrylate injection for gastric variceal bleeding. METHODS: Patients with cirrhosis who underwent endoscopic cyanoacrylate injection for gastric variceal bleeding were included. Patients with cirrhosis who underwent upper endoscopy for nonvariceal upper GI bleeding were recruited as controls. Patients with infection before endoscopy were excluded. Blood was cultured in both groups. Injection needles and endoscope accessory channels were cultured in the cyanoacrylate injection group. RESULTS: More patients injected with cyanoacrylate had positive blood cultures in comparison with the control group (15/47 vs. 1/47, p < 0.0001). In the cyanoacrylate injection group, the volume of blood transfused and Child-Pugh score were factors associated with the occurrence of bacteremia. Most episodes of bacteremia were transient, except for 1 patient who died of sepsis. Most of the microorganisms cultured from blood samples were identical to those cultured from injection needles (65%) and accessory channels (90%). CONCLUSIONS: Endoscopic cyanoacrylate injection for gastric varices does not limit the spread of bacteria. The endoscope accessory channel was the major source of bacteria. Most episodes of bacteremia were transient and uneventful.

Adaptive vasodilatory response after octreotide treatment.

Despite the suppression of glucagon release, an adaptive response aimed at maintaining vasodilatation after octreotide treatment may exist in portal hypertension. The present study was undertaken to evaluate the possible interaction between endothelium and non-endothelium-derived vasodilators after 1-wk octreotide administration in cirrhotic rats. Rats were allocated to receive either vehicle or octreotide (30 or 100 microg/kg every 12 h subcutaneously). Hemodynamic values, plasma glucagon levels, endothelium-related vasodilatory activities, and aortic endothelial nitric oxide synthase (eNOS) expression were determined after treatment. Octreotide administration decreased plasma glucagon and increased serum 6-keto-PGF(1 alpha) and NOx levels without affecting the hemodynamic values. In cirrhotic rats receiving octreotide, there was a blunt response to either L-NAME or indomethacin administration alone, but this blunt pressor response disappeared after simultaneous administration of the two drugs. Additionally, an increased aortic eNOS expression was observed in cirrhotic rats receiving 1-wk octreotide. It is concluded that 1-wk octreotide treatment did not correct the hemodynamic derangement in cirrhotic rats. The enhanced endothelium-related vasodilatory activity was noted after octreotide treatment that overcame the octreotide-induced hemodynamic effects in portal hypertension.

Feasibility and potential benefit of maintenance endoscopic variceal ligation in patients with unresectable hepatocellular carcinoma and acute esophageal variceal hemorrhage: a controlled trial.

BACKGROUND: Patients with unresectable hepatoma and acute esophageal variceal bleeding have extremely high rates of recurrent bleeding and mortality. This controlled study evaluates the feasibility and potential benefit of maintenance endoscopic variceal ligation in these patients. METHODS: Patients with unresectable hepatoma and acute esophageal variceal bleeding underwent emergent endoscopic variceal ligation. After hemostasis, patients were randomized to undergo maintenance or esophageal variceal ligation (EVL) as necessary (demand ligation). RESULTS: Fifty-four patients underwent maintenance EVL and 55 demanded EVL. One or more subsequent EVL session could be performed in only 30 patients (55.6%) in the maintenance group (actual maintenance ligation). Logistic regression analysis found that hepatic function determines the feasibility of maintenance ligation (Child-Pugh's A+B vs. C, OR 23.00: 95% CI [5.26, 100.66]). The survival and recurrent bleeding rates were similar in both groups. A subgroup analysis of patients with Child-Pugh's A and B hepatic reserve in both the maintenance EVL group (n = 24) and demand EVL group (n = 25) was performed to assess the potential benefit of maintenance ligation. Maintenance ligation reduced the rate of recurrent bleeding compared with demand ligation (p = 0.043). Cox regression showed that portal vein thrombosis and tumors in both hepatic lobes were also factors together with EVL that determined recurrence of bleeding. Survival was similar in both groups. CONCLUSIONS: Maintenance ligation is feasible in patients with unresectable hepatoma and variceal hemorrhage if they have a good hepatic reserve. Maintenance ligation might lower the rate of recurrent bleeding in this subgroup of patients.