AIM:To evaluate the incidence and clinical characteristics of gastric cancer(GC) in peptic ulcer patients with Helicobacter pylori(H.pylori) infection.METHODS:Between January 2003 and December 2013, the medical record...AIM:To evaluate the incidence and clinical characteristics of gastric cancer(GC) in peptic ulcer patients with Helicobacter pylori(H.pylori) infection.METHODS:Between January 2003 and December 2013, the medical records of patients diagnosed with GC were retrospectively reviewed.Those with previous gastric ulcer(GU) and H.pylori infection were assigned to the Hp GU-GC group(n = 86) and those with previous duodenal ulcer(DU) disease and H.pylori infection were assigned to the Hp DUGC group(n = 35).The incidence rates of GC in the Hp GU-GC and Hp DU-GC groups were analyzed.Data on demographics(age, gender, peptic ulcer complications and cancer treatment), GC clinical characteristics [location, pathological diagnosis, differentiation, T stage, Lauren's classification, atrophy of surrounding mucosa and intestinal metaplasia(IM)], outcome of eradication therapy for H.pylori infection, esophagogastroduodenoscopy number and the duration until GC onset were reviewed.Univariate and multivariate analyses were performed to identify factors influencing GC development.The relative risk of GC was evaluated using a Cox proportional hazards model.RESULTS:The incidence rates of GC were 3.60%(86/2387) in the Hp GU-GC group and 1.66%(35/2098) in the Hp DU-GC group.The annual incidence was 0.41% in the Hp GU-GC group and 0.11% in the Hp DUGC group.The rates of moderate-to-severe atrophy of the surrounding mucosa and IM were higher in the Hp GU-GC group than in the Hp DU-GC group(86% vs 34.3%, respectively, and 61.6% vs 14.3%, respectively, P < 0.05).In the univariate analysis, atrophy of surrounding mucosa, IM and eradication therapy for H.pylori infection were significantly associated with the development of GC(P < 0.05).There was no significant difference in the prognosis of GC patients between the Hp GU-GC and Hp DU-GC groups(P = 0.347).The relative risk of GC development in the Hp GUGC group compared to that of the Hp DU-GC group,after correction for age and gender,was 1.71(95%CI:1.09-2.70;P=0.02).CONCLUSION:GU patients with H.pylori infection had higher GC incidence rates and relative risks.Atrophy of surrounding mucosa,IM and eradication therapy were associated with GC.展开更多
AIM: To investigate the eradication rate and histological changes after Helicobacter pylori(H. pylori) eradication treatment following subtotal gastrectomy for gastric cancer.METHODS: A total of 610 patients with H. p...AIM: To investigate the eradication rate and histological changes after Helicobacter pylori(H. pylori) eradication treatment following subtotal gastrectomy for gastric cancer.METHODS: A total of 610 patients with H. pylori infection who had undergone surgery for either early or advanced gastric adenocarcinoma between May 2004 and December 2010 were retrospectively studied. A total of 584 patients with proven H. pylori infection after surgery for gastric cancer were enrolled in this study. Patients received a seven day standard triple regimen as first-line therapy and a 10 d bismuthcontaining quadruple regimen as second-line therapy in cases of eradication failure. The patients underwent an esophagogastroduodenoscopy(EGD) between six and 12 mo after surgery, followed by annual EGDs. A further EGD was conducted 12 mo after confirming the result of the eradication and the histological changes. A gastric biopsy specimen for histological examination and Campylobacter-like organism testing was obtained from the lesser and greater curvature of the corpus of the remnant stomach. Histological changes in the gastric mucosa were assessed using the updated Sydney system before eradication therapy and at follow-up after 12 mo.RESULTS: Eradication rates with the first-line and second-line therapies were 78.4%(458/584) and 90%(36/40), respectively, by intention-to-treat analysis and 85.3%(458/530) and 92.3%(36/39), respectively, by per-protocol analysis. The univariate and multivariate analyses revealed that Billroth Ⅱ surgery was an independent factor predictive of eradication success in the eradication success group(OR = 1.53, 95%CI: 1.41-1.65, P = 0.021). The atrophy and intestinal metaplasia(IM) scores 12 mo after eradication were significantly lower in the eradication success group than in the eradication failure group(0.25 ± 0.04 vs 0.47 ± 0.12, P = 0.023; 0.27 ± 0.04 vs 0.51 ± 0.12, P = 0.015, respectively). The atrophy and IM scores 12 mo after successful eradication were significantly lower in the Billroth Ⅱ group than in the Billroth I group(0.13 ± 0.09 vs 0.31 ± 0.12, P = 0.029; 0.32 ± 0.24 vs 0.37 ± 0.13, P = 0.034, respectively).CONCLUSION: Patients with H. pylori following subtotal gastrectomy had a similar eradication rate to patients with an intact stomach. H. pylori eradication is recommended after subtotal gastrectomy.展开更多
AIM: To compare the efficacy of 14- and 7-d bismuthbased quadruple therapies as second-line eradication treatment for Helicobacter pylori(H.pylori) infection.METHODS: Between 2004 and 2014,the medical records of 790 p...AIM: To compare the efficacy of 14- and 7-d bismuthbased quadruple therapies as second-line eradication treatment for Helicobacter pylori(H.pylori) infection.METHODS: Between 2004 and 2014,the medical records of 790 patients who had experienced failure of first-line proton pump inhibitor(PPI)-based eradication therapy and were then treated with bismuth-based quadruple therapy were retrospectively reviewed.Those who received bismuth-based quadruple therapy [PPI,bismuth,metronidazole,and tetracycline(PBMT)] for either 7 d or 14 d were assigned to a PBMT-7 group(n = 543) or a PBMT-14 group(n = 247),respectively.The eradication rates for both groups were determined by intention-to-treat(ITT) and per-protocol(PP) analyses.ITT analysis compared the treatment groups as originally allocated while the PP analysis including only those patients who had completed the treatment as originally allocated.Successful eradication therapy for H.pylori infection was defined as a negative 13C-urea breath test 4 wk after the end of eradication treatment.RESULTS: The overall ITT eradication rate was 69.1%(546/790).Final ITT eradication rates were 67.4%(366/543; 95%CI: 63.1%-71.7%) in the PBMT-7 group and 72.8%(180/247; 95%CI: 67.4%-78.2%) in the PBMT-14 group(P = 0.028).The overall PP eradication rate was 80.0%(546/682),and the final PP eradication rates were 78.2%(366/468; 95%CI: 72.1%-84.0%) in the PBMT-7 group and 84.1%(180/214; 95%CI: 76.8%-90.8%) in the PBMT-14 group(P = 0.009).The H.pylori eradication rates in the PBMT-14 group weresignificantly higher than in the PBMT-7 group according to both ITT(P = 0.028) and PP analysis(P = 0.009).Compliance was similar in both groups(PBMT-7 group: 97.9%; PBMT-14 group: 96.4%).Adverse event rates were 10.7%(51/478) and 17.1%(38/222) in the PBMT-7 and PBMT-14 groups,respectively(P = 0.487).CONCLUSION: The 14-d bismuth-based quadruple therapy is a significantly more effective second-line eradication treatment for H.pylori infection than the 7-d alternative.展开更多
AIM:To evaluate the efficacy of 14-d moxifloxacinbased sequential therapy as first-line eradication treatment of Helicobacter pylori(H.pylori) infection.METHODS:From December 2013 to August 2014, 161 patients with con...AIM:To evaluate the efficacy of 14-d moxifloxacinbased sequential therapy as first-line eradication treatment of Helicobacter pylori(H.pylori) infection.METHODS:From December 2013 to August 2014, 161 patients with confirmed H.pylori infection randomly received 14 d of moxifloxacin-based sequential group(MOX-ST group, n = 80) or clarithromycin-based sequential group(CLA-ST group, n = 81) therapy.H.pylori infection was defined on the basis of at least one of the following three tests:a positive 13C-urea breath test; histologic evidence of H.pylori by modified Giemsa staining; or a positive rapid urease test(CLOtest; Delta West, Bentley, Australia) by gastric mucosal biopsy.Successful eradication therapy for H.pylori infection was defined as a negative 13C-urea breath test four weeks after the end of eradication treatment.Compliance was defined as good when drug intake was at least 85%.H.pylori eradication rates, patient compliance with drug treatment, adverse event rates, and factors influencing the efficacy of eradication therapy were evaluated.RESULTS:The eradication rates by intention-to-treat analysis were 91.3%(73/80;95%CI:86.2%-95.4%)in the MOX-ST group and 71.6%(58/81;95%CI:65.8%-77.4%)in the CLA-ST group(P=0.014).The eradication rates by per-protocol analysis were 93.6%(73/78;95%CI:89.1%-98.1%)in the MOX-ST group and 75.3%(58/77;95%CI:69.4%-81.8%)in the CLAST group(P=0.022).Compliance was 100%in both groups.The adverse event rates were 12.8%(10/78)and 24.6%(19/77)in the MOX-ST and CLA-ST group,respectively(P=0.038).Most of the adverse events were mild-to-moderate in intensity;there was none serious enough to cause discontinuation of treatmentin either group.In multivariate analysis,advanced age(≥60 years)was a significant independent factor related to the eradication failure in the CLA-ST group(adjusted OR=2.13,95%CI:1.97-2.29,P=0.004),whereas there was no significance in the MOX-ST group.CONCLUSION:The 14-d moxifloxacin-based sequential therapy is effective.Moreover,it shows excellent patient compliance and safety compared to the 14-d clarithromycin-based sequential therapy.展开更多
AIM: To evaluate the efficacy of moxifloxacin-based sequential therapy(MBST) versus hybrid therapy as a first-line treatment for Helicobacter pylori(H. pylori) infection.METHODS: From August 2014 to January 2015, 284 ...AIM: To evaluate the efficacy of moxifloxacin-based sequential therapy(MBST) versus hybrid therapy as a first-line treatment for Helicobacter pylori(H. pylori) infection.METHODS: From August 2014 to January 2015, 284 patients with confirmed H. pylori infection were randomized to receive a 14-d course of MBST(MBST group, n = 140) or hybrid(Hybrid group, n = 144) therapy. The MBST group received 20 mg rabeprazole and 1 g amoxicillin twice daily for 7 d, followed by 20 mg rabeprazole and 500 mg metronidazole twice daily, and 400 mg moxifloxacin once daily for 7 d. The Hybrid group received 20 mg rabeprazole and 1 g amoxicillin twice daily for 14 d. In addition, the Hybrid group received 500 mg metronidazole and 500 mg clarithromycin twice daily for the final 7 d. Successful eradication of H. pylori infection was defined as a negative 13C-urea breath test 4 wk after the end of treatment. Patient compliance was defined as "good" if drug intake was at least 85%. H. pylori eradication rates, patient compliance with treatment, and adverse event rates were evaluated.RESULTS: The eradication rates in the intention-totreat(ITT) analysis were 91.4%(128/140; 95%CI: 90.2%-92.9%) in the MBST group and 79.2%(114/144; 95%CI: 77.3%-80.7%) in the Hybrid group(P = 0.013). The eradication rates in the perprotocol(PP) analysis were 94.1%(128/136; 95%CI: 92.9%-95.6%) in the MBST group and 82.6%(114/138; 95%CI: 80.6%-84.1%) in the Hybrid group(P = 0.003). The H. pylori eradication rate in the MBST group was significantly higher than that of the Hybrid group for both the ITT(P = 0.013) and the PP analyses(P = 0.003). Both groups exhibited full compliance with treatment(MBST/Hybrid group: 100%/100%). The rate of adverse events was 11.8%(16/136) and 19.6%(27/138) in the MBST and Hybrid group, respectively(P = 0.019). The majority of adverse events were mild-to-moderate in intensity; none were severe enough to cause discontinuation of treatment in either group.CONCLUSION: MBST was more effective and led to fewer adverse events than hybrid therapy as a first-line treatment for H. pylori infection.展开更多
BACKGROUND Drug-induced liver injury(DILI)is the leading cause of acute liver failure in the United States.DILI is mainly caused by painkillers and fever reducers,and it is often characterized by the type of hepatic i...BACKGROUND Drug-induced liver injury(DILI)is the leading cause of acute liver failure in the United States.DILI is mainly caused by painkillers and fever reducers,and it is often characterized by the type of hepatic injury(hepatocellular or cholestatic).This report presents a case of fenofibrate-induced severe jaundice in a 65-year-old Korean male with no prior history of liver disease.We offer a strategy for patients who present signs of severe liver injury with jaundice and high elevations in serum transaminases.CASE SUMMARY A 65-year-old male visited the gastroenterology outpatient clinic of a tertiary hospital due to increased levels of liver enzyme and total bilirubin which were incidentally detected through a preoperative screening test.Abdominal ultrasound and computed tomography showed no biliary obstruction or nonspecific findings in the liver.Liver biopsy was performed and the patient was finally diagnosed with acute cholestatic hepatitis.Following the biopsy,steroid therapy was initiated and after 3 wk of treatment,the total bilirubin level was reduced to 7.22 mg/dL.CONCLUSION In patients with hyperlipidemia,treatment including fenofibric acid induces rare complications such as severe jaundice and acute cholestatic hepatitis,warranting clinical attention.展开更多
文摘AIM:To evaluate the incidence and clinical characteristics of gastric cancer(GC) in peptic ulcer patients with Helicobacter pylori(H.pylori) infection.METHODS:Between January 2003 and December 2013, the medical records of patients diagnosed with GC were retrospectively reviewed.Those with previous gastric ulcer(GU) and H.pylori infection were assigned to the Hp GU-GC group(n = 86) and those with previous duodenal ulcer(DU) disease and H.pylori infection were assigned to the Hp DUGC group(n = 35).The incidence rates of GC in the Hp GU-GC and Hp DU-GC groups were analyzed.Data on demographics(age, gender, peptic ulcer complications and cancer treatment), GC clinical characteristics [location, pathological diagnosis, differentiation, T stage, Lauren's classification, atrophy of surrounding mucosa and intestinal metaplasia(IM)], outcome of eradication therapy for H.pylori infection, esophagogastroduodenoscopy number and the duration until GC onset were reviewed.Univariate and multivariate analyses were performed to identify factors influencing GC development.The relative risk of GC was evaluated using a Cox proportional hazards model.RESULTS:The incidence rates of GC were 3.60%(86/2387) in the Hp GU-GC group and 1.66%(35/2098) in the Hp DU-GC group.The annual incidence was 0.41% in the Hp GU-GC group and 0.11% in the Hp DUGC group.The rates of moderate-to-severe atrophy of the surrounding mucosa and IM were higher in the Hp GU-GC group than in the Hp DU-GC group(86% vs 34.3%, respectively, and 61.6% vs 14.3%, respectively, P < 0.05).In the univariate analysis, atrophy of surrounding mucosa, IM and eradication therapy for H.pylori infection were significantly associated with the development of GC(P < 0.05).There was no significant difference in the prognosis of GC patients between the Hp GU-GC and Hp DU-GC groups(P = 0.347).The relative risk of GC development in the Hp GUGC group compared to that of the Hp DU-GC group,after correction for age and gender,was 1.71(95%CI:1.09-2.70;P=0.02).CONCLUSION:GU patients with H.pylori infection had higher GC incidence rates and relative risks.Atrophy of surrounding mucosa,IM and eradication therapy were associated with GC.
文摘AIM: To investigate the eradication rate and histological changes after Helicobacter pylori(H. pylori) eradication treatment following subtotal gastrectomy for gastric cancer.METHODS: A total of 610 patients with H. pylori infection who had undergone surgery for either early or advanced gastric adenocarcinoma between May 2004 and December 2010 were retrospectively studied. A total of 584 patients with proven H. pylori infection after surgery for gastric cancer were enrolled in this study. Patients received a seven day standard triple regimen as first-line therapy and a 10 d bismuthcontaining quadruple regimen as second-line therapy in cases of eradication failure. The patients underwent an esophagogastroduodenoscopy(EGD) between six and 12 mo after surgery, followed by annual EGDs. A further EGD was conducted 12 mo after confirming the result of the eradication and the histological changes. A gastric biopsy specimen for histological examination and Campylobacter-like organism testing was obtained from the lesser and greater curvature of the corpus of the remnant stomach. Histological changes in the gastric mucosa were assessed using the updated Sydney system before eradication therapy and at follow-up after 12 mo.RESULTS: Eradication rates with the first-line and second-line therapies were 78.4%(458/584) and 90%(36/40), respectively, by intention-to-treat analysis and 85.3%(458/530) and 92.3%(36/39), respectively, by per-protocol analysis. The univariate and multivariate analyses revealed that Billroth Ⅱ surgery was an independent factor predictive of eradication success in the eradication success group(OR = 1.53, 95%CI: 1.41-1.65, P = 0.021). The atrophy and intestinal metaplasia(IM) scores 12 mo after eradication were significantly lower in the eradication success group than in the eradication failure group(0.25 ± 0.04 vs 0.47 ± 0.12, P = 0.023; 0.27 ± 0.04 vs 0.51 ± 0.12, P = 0.015, respectively). The atrophy and IM scores 12 mo after successful eradication were significantly lower in the Billroth Ⅱ group than in the Billroth I group(0.13 ± 0.09 vs 0.31 ± 0.12, P = 0.029; 0.32 ± 0.24 vs 0.37 ± 0.13, P = 0.034, respectively).CONCLUSION: Patients with H. pylori following subtotal gastrectomy had a similar eradication rate to patients with an intact stomach. H. pylori eradication is recommended after subtotal gastrectomy.
文摘AIM: To compare the efficacy of 14- and 7-d bismuthbased quadruple therapies as second-line eradication treatment for Helicobacter pylori(H.pylori) infection.METHODS: Between 2004 and 2014,the medical records of 790 patients who had experienced failure of first-line proton pump inhibitor(PPI)-based eradication therapy and were then treated with bismuth-based quadruple therapy were retrospectively reviewed.Those who received bismuth-based quadruple therapy [PPI,bismuth,metronidazole,and tetracycline(PBMT)] for either 7 d or 14 d were assigned to a PBMT-7 group(n = 543) or a PBMT-14 group(n = 247),respectively.The eradication rates for both groups were determined by intention-to-treat(ITT) and per-protocol(PP) analyses.ITT analysis compared the treatment groups as originally allocated while the PP analysis including only those patients who had completed the treatment as originally allocated.Successful eradication therapy for H.pylori infection was defined as a negative 13C-urea breath test 4 wk after the end of eradication treatment.RESULTS: The overall ITT eradication rate was 69.1%(546/790).Final ITT eradication rates were 67.4%(366/543; 95%CI: 63.1%-71.7%) in the PBMT-7 group and 72.8%(180/247; 95%CI: 67.4%-78.2%) in the PBMT-14 group(P = 0.028).The overall PP eradication rate was 80.0%(546/682),and the final PP eradication rates were 78.2%(366/468; 95%CI: 72.1%-84.0%) in the PBMT-7 group and 84.1%(180/214; 95%CI: 76.8%-90.8%) in the PBMT-14 group(P = 0.009).The H.pylori eradication rates in the PBMT-14 group weresignificantly higher than in the PBMT-7 group according to both ITT(P = 0.028) and PP analysis(P = 0.009).Compliance was similar in both groups(PBMT-7 group: 97.9%; PBMT-14 group: 96.4%).Adverse event rates were 10.7%(51/478) and 17.1%(38/222) in the PBMT-7 and PBMT-14 groups,respectively(P = 0.487).CONCLUSION: The 14-d bismuth-based quadruple therapy is a significantly more effective second-line eradication treatment for H.pylori infection than the 7-d alternative.
文摘AIM:To evaluate the efficacy of 14-d moxifloxacinbased sequential therapy as first-line eradication treatment of Helicobacter pylori(H.pylori) infection.METHODS:From December 2013 to August 2014, 161 patients with confirmed H.pylori infection randomly received 14 d of moxifloxacin-based sequential group(MOX-ST group, n = 80) or clarithromycin-based sequential group(CLA-ST group, n = 81) therapy.H.pylori infection was defined on the basis of at least one of the following three tests:a positive 13C-urea breath test; histologic evidence of H.pylori by modified Giemsa staining; or a positive rapid urease test(CLOtest; Delta West, Bentley, Australia) by gastric mucosal biopsy.Successful eradication therapy for H.pylori infection was defined as a negative 13C-urea breath test four weeks after the end of eradication treatment.Compliance was defined as good when drug intake was at least 85%.H.pylori eradication rates, patient compliance with drug treatment, adverse event rates, and factors influencing the efficacy of eradication therapy were evaluated.RESULTS:The eradication rates by intention-to-treat analysis were 91.3%(73/80;95%CI:86.2%-95.4%)in the MOX-ST group and 71.6%(58/81;95%CI:65.8%-77.4%)in the CLA-ST group(P=0.014).The eradication rates by per-protocol analysis were 93.6%(73/78;95%CI:89.1%-98.1%)in the MOX-ST group and 75.3%(58/77;95%CI:69.4%-81.8%)in the CLAST group(P=0.022).Compliance was 100%in both groups.The adverse event rates were 12.8%(10/78)and 24.6%(19/77)in the MOX-ST and CLA-ST group,respectively(P=0.038).Most of the adverse events were mild-to-moderate in intensity;there was none serious enough to cause discontinuation of treatmentin either group.In multivariate analysis,advanced age(≥60 years)was a significant independent factor related to the eradication failure in the CLA-ST group(adjusted OR=2.13,95%CI:1.97-2.29,P=0.004),whereas there was no significance in the MOX-ST group.CONCLUSION:The 14-d moxifloxacin-based sequential therapy is effective.Moreover,it shows excellent patient compliance and safety compared to the 14-d clarithromycin-based sequential therapy.
文摘AIM: To evaluate the efficacy of moxifloxacin-based sequential therapy(MBST) versus hybrid therapy as a first-line treatment for Helicobacter pylori(H. pylori) infection.METHODS: From August 2014 to January 2015, 284 patients with confirmed H. pylori infection were randomized to receive a 14-d course of MBST(MBST group, n = 140) or hybrid(Hybrid group, n = 144) therapy. The MBST group received 20 mg rabeprazole and 1 g amoxicillin twice daily for 7 d, followed by 20 mg rabeprazole and 500 mg metronidazole twice daily, and 400 mg moxifloxacin once daily for 7 d. The Hybrid group received 20 mg rabeprazole and 1 g amoxicillin twice daily for 14 d. In addition, the Hybrid group received 500 mg metronidazole and 500 mg clarithromycin twice daily for the final 7 d. Successful eradication of H. pylori infection was defined as a negative 13C-urea breath test 4 wk after the end of treatment. Patient compliance was defined as "good" if drug intake was at least 85%. H. pylori eradication rates, patient compliance with treatment, and adverse event rates were evaluated.RESULTS: The eradication rates in the intention-totreat(ITT) analysis were 91.4%(128/140; 95%CI: 90.2%-92.9%) in the MBST group and 79.2%(114/144; 95%CI: 77.3%-80.7%) in the Hybrid group(P = 0.013). The eradication rates in the perprotocol(PP) analysis were 94.1%(128/136; 95%CI: 92.9%-95.6%) in the MBST group and 82.6%(114/138; 95%CI: 80.6%-84.1%) in the Hybrid group(P = 0.003). The H. pylori eradication rate in the MBST group was significantly higher than that of the Hybrid group for both the ITT(P = 0.013) and the PP analyses(P = 0.003). Both groups exhibited full compliance with treatment(MBST/Hybrid group: 100%/100%). The rate of adverse events was 11.8%(16/136) and 19.6%(27/138) in the MBST and Hybrid group, respectively(P = 0.019). The majority of adverse events were mild-to-moderate in intensity; none were severe enough to cause discontinuation of treatment in either group.CONCLUSION: MBST was more effective and led to fewer adverse events than hybrid therapy as a first-line treatment for H. pylori infection.
基金Supported by Soonchunhyang University Research Fund,No.20200037.
文摘BACKGROUND Drug-induced liver injury(DILI)is the leading cause of acute liver failure in the United States.DILI is mainly caused by painkillers and fever reducers,and it is often characterized by the type of hepatic injury(hepatocellular or cholestatic).This report presents a case of fenofibrate-induced severe jaundice in a 65-year-old Korean male with no prior history of liver disease.We offer a strategy for patients who present signs of severe liver injury with jaundice and high elevations in serum transaminases.CASE SUMMARY A 65-year-old male visited the gastroenterology outpatient clinic of a tertiary hospital due to increased levels of liver enzyme and total bilirubin which were incidentally detected through a preoperative screening test.Abdominal ultrasound and computed tomography showed no biliary obstruction or nonspecific findings in the liver.Liver biopsy was performed and the patient was finally diagnosed with acute cholestatic hepatitis.Following the biopsy,steroid therapy was initiated and after 3 wk of treatment,the total bilirubin level was reduced to 7.22 mg/dL.CONCLUSION In patients with hyperlipidemia,treatment including fenofibric acid induces rare complications such as severe jaundice and acute cholestatic hepatitis,warranting clinical attention.
