Mid- to Long-Term Outcomes in Management of Spontaneous Isolated Coeliac Artery Dissection (SICAD).

OBJECTIVE: Spontaneous Isolated Coeliac Artery Dissection (SICAD) is a rare disease with few reports of management strategies. This study reports the mid- to long-term outcomes of conservative management and endovascular intervention of SICAD treatment. METHODS: Sixteen patients presenting with symptomatic SICAD from September 2006 to October 2018 were reviewed retrospectively. The clinical manifestations, initial radiological findings, methods of treatment, and serial follow up studies were analysed. RESULTS: The mean age of the patients was 51.2 ± 7.9 years, with a median follow up of 33.3 (range 1.0-118.9) months. Four patients received early intervention because of aneurysmal dilatation or distal hypoperfusion. Four patients who received conservative management showed progression of disease and were recommended for delayed intervention. Although collaterals prevented further hepatic ischaemia, one of these four patients failed in delayed intervention because of extensive thrombi completely occluding the hepatic artery. In the remaining eight patients who were managed conservatively, three (37.5%) showed regression of disease, one (12.5%) showed partial regression, and five (62.5%) showed no change in intimal flap or thrombosis, but all had symptomatic improvement. The median follow up duration for the seven patients who underwent successful intervention was 77.3 (range 34.3-118.9) months, and all stenting remained patent during the follow up period. CONCLUSION: Early intervention in symptomatic SICAD patients may be necessary in over 50% of patients, and endovascular stenting has durable long term outcomes.

Pyronaridine-artesunate versus mefloquine plus artesunate for malaria.

BACKGROUND: Pyronaridine-artesunate is an artemisinin-based combination therapy under evaluation for the treatment of Plasmodium falciparum and P. vivax malaria. METHODS: We conducted a phase 3, open-label, multicenter, noninferiority trial that included 1271 patients between 3 and 60 years of age from Asia (81.3%) or Africa (18.7%) with microscopically confirmed, uncomplicated P. falciparum malaria. Patients underwent randomization for treatment with a fixed-dose combination of 180 mg of pyronaridine and 60 mg of artesunate or with 250 mg of mefloquine plus 100 mg of artesunate. Doses were calculated according to body weight and administered once daily for 3 days. RESULTS: Pyronaridine-artesunate was noninferior to mefloquine plus artesunate for the primary outcome: adequate clinical and parasitologic response in the per-protocol population on day 28, corrected for reinfection with the use of polymerase-chain-reaction (PCR) genotyping. For this outcome, efficacy in the group receiving pyronaridine-artesunate was 99.2% (743 of 749 patients; 95% confidence interval [CI], 98.3 to 99.7) and that in the group receiving mefloquine plus artesunate was 97.8% (360 of 368 patients; 95% CI, 95.8 to 99.1), with a treatment difference of 1.4 percentage points (95% CI, 0.0 to 3.5; P=0.05). In the intention-to-treat population, efficacy on day 42 in the group receiving pyronaridine-artesunate was 83.1% (705 of 848 patients; 95% CI, 80.4 to 85.6) and that in the group receiving mefloquine plus artesunate was 83.9% (355 of 423 patients; 95% CI, 80.1 to 87.3). In Cambodia, where there were 211 study patients, the median parasite clearance time was prolonged for both treatments: 64 hours versus 16.0 to 38.9 hours in other countries (P<0.001, on the basis of Kaplan-Meier estimates). Kaplan-Meier estimates of the recrudescence rate in the intention-to-treat population in Cambodia until day 42 were higher with pyronaridine-artesunate than with mefloquine plus artesunate (10.2% [95% CI, 5.4 to 18.6] vs. 0%; P=0.04 as calculated with the log-rank test), but similar for the other countries combined (4.7% [95% CI, 3.3 to 6.7] and 2.8% [95% CI, 1.5 to 5.3], respectively; P=0.24). Elevated levels of aminotransferases were observed in those receiving pyronaridine-artesunate. Two patients receiving mefloquine plus artesunate had seizures. CONCLUSIONS: Fixed-dose pyronaridine-artesunate was efficacious in the treatment of uncomplicated P. falciparum malaria. In Cambodia, extended parasite clearance times were suggestive of in vivo resistance to artemisinin. (Funded by Shin Poong Pharmaceutical Company and the Medicines for Malaria Venture; ClinicalTrials.gov number, NCT00403260.).

The Incidence and Characteristics of Pelvic-Origin Varicosities in Patients with Complex Varices Evaluated by Ultrasonography.

OBJECTIVE: The purpose of this study was to evaluate the incidence of gonadal vein refluxes associated with lower-extremity varicose veins with Doppler ultrasonography (DUS). METHOD: A total of 6279 patients with venous disease-related symptoms of the lower extremity were evaluated with DUS in the vascular lab. Gonadal vein reflux using abdominal ultrasound was further evaluated in patients with unusual varices, defined as varices in the inguinal, inner or upper thigh and the vulvar area without refluxes in the saphenofemoral junction (SPJ). Those patients who showed gonadal vein reflux were diagnosed as having pelvic-origin varicosity. RESULTS: Unusual varices were found in a total of 237 patients (3.8%), and of these patients, pelvic-origin varicosity was discovered with transabdominal ultrasound in 156 (65.8%). A total of 66.7% (n = 38/57) of unusual varix patients with pelvic pain had gonadal vein reflux. The measurement of gonadal vein diameter was larger in ultrasonography than CT scans (8.835 vs. 8.81, p < 0.001). Two patients with severe symptoms but no obstructive venous diseases were treated with gonadal vein embolization. CONCLUSION: The incidence of pelvic-origin varicosities was 2.5% (n = 156/6279). However, more than half of the patients with unusual varices had gonadal vein reflux and 24.4% of these patients also presented with pelvic pain. The evaluation of pelvic-origin varicosities should be performed in patients who present with unusual forms of varices of the lower extremity.

Effects of body size and gender on the population pharmacokinetics of artesunate and its active metabolite dihydroartemisinin in pediatric malaria patients.

Despite the important role of the antimalarial artesunate and its active metabolite dihydroartemisinin (DHA) in malaria treatment efforts, there are limited data on the pharmacokinetics of these agents in pediatric patients. This study evaluated the effects of body size and gender on the pharmacokinetics of artesunate-DHA using data from pediatric and adult malaria patients. Nonlinear mixed-effects modeling was used to obtain a base model consisting of first-order artesunate absorption and one-compartment models for artesunate and for DHA. Various methods of incorporating effects of body size descriptors on clearance and volume parameters were tested. An allometric scaling model for weight and a linear body surface area (BSA) model were deemed optimal. The apparent clearance and volume of distribution of DHA obtained with the allometric scaling model, normalized to a 38-kg patient, were 63.5 liters/h and 65.1 liters, respectively. Estimates for the linear BSA model were similar. The 95% confidence intervals for the estimated gender effects on clearance and volume parameters for artesunate fell outside the predefined no-relevant-clinical-effect interval of 0.75 to 1.25. However, the effect of gender on apparent DHA clearance was almost entirely contained within this interval, suggesting a lack of an influence of gender on this parameter. Overall, the pharmacokinetics of artesunate and DHA following oral artesunate administration can be described for pediatric patients using either an allometric scaling or linear BSA model. Both models predict that, for a given artesunate dose in mg/kg of body weight, younger children are expected to have lower DHA exposure than older children or adults.

Safety and efficacy of pyronaridine-artesunate in uncomplicated acute malaria: an integrated analysis of individual patient data from six randomized clinical trials.

BACKGROUND: Pyronaridine-artesunate (PA) is indicated for the treatment of acute uncomplicated Plasmodium falciparum and Plasmodium vivax malaria. METHODS: Individual patient data on safety outcomes were integrated from six randomized clinical trials conducted in Africa and Asia in patients with microscopically confirmed P. falciparum (five studies) or P. vivax (one study) malaria. Efficacy against P. falciparum was evaluated across three Phase III clinical trials. RESULTS: The safety population included 2,815 patients randomized to PA, 1,254 to comparators: mefloquine + artesunate (MQ + AS), artemether-lumefantrine (AL), or chloroquine. All treatments were generally well tolerated. Adverse events occurred in 57.2% (1,611/2,815) of patients with PA versus 51.5% (646/1,254) for comparators, most commonly (PA; comparators): headache (10.6%; 9.9%), cough (5.9%; 5.6%) and anaemia (4.5%; 2.9%). Serious averse events were uncommon for all treatments (0-0.7%). Transient increases in alanine aminotransferase and aspartate aminotransferase were observed with PA but did not lead to any clinical sequelae. For P. falciparum malaria, day-28 PCR-corrected adequate clinical and parasitological response with PA was 93.6% ([1,921/2,052] 95% CI 92.6, 94.7) in the intent-to-treat population and 98.5% ([1,852/1,880] 95% CI 98.0, 99.1) in the per-protocol population. Median parasite clearance time was 24.1 h with PA, 31.9 h with MQ + AS, and 24.0 h with AL. Median fever clearance time was 15.5 h with PA, 15.8 h with MQ + AS, and 14.0 h with AL. By day 42, P. falciparum gametocytes had declined to near zero for all treatments. CONCLUSIONS: Pyronaridine-artesunate was well tolerated with no safety concerns with the exception of mostly mild transient rises in transaminases. Efficacy was high and met the requirements for use as first-line therapy. Pyronaridine-artesunate should be considered for inclusion in malaria treatment programmes. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00331136; NCT00403260; NCT00422084; NCT00440999; NCT00541385; NCT01594931.

Review of pyronaridine anti-malarial properties and product characteristics.

Pyronaridine was synthesized in 1970 at the Institute of Chinese Parasitic Disease and has been used in China for over 30 years for the treatment of malaria. Pyronaridine has high potency against Plasmodium falciparum, including chloroquine-resistant strains. Studies in various animal models have shown pyronaridine to be effective against strains resistant to other anti-malarials, including chloroquine. Resistance to pyronaridine appears to emerge slowly and is further retarded when pyronaridine is used in combination with other anti-malarials, in particular, artesunate. Pyronaridine toxicity is generally less than that of chloroquine, though evidence of embryotoxicity in rodents suggests use with caution in pregnancy. Clinical pharmacokinetic data for pyronaridine indicates an elimination T1/2 of 13.2 and 9.6 days, respectively, in adults and children with acute uncomplicated falciparum and vivax malaria in artemisinin-combination therapy. Clinical data for mono or combined pyronaridine therapy show excellent anti-malarial effects against P. falciparum and studies of combination therapy also show promise against Plasmodium vivax. Pyronaridine has been developed as a fixed dose combination therapy, in a 3:1 ratio, with artesunate for the treatment of acute uncomplicated P. falciparum malaria and blood stage P. vivax malaria with the name of Pyramax® and has received Positive Opinion by European Medicines Agency under the Article 58 procedure.

Pyronaridine-artesunate granules versus artemether-lumefantrine crushed tablets in children with Plasmodium falciparum malaria: a randomized controlled trial.

BACKGROUND: Children are most vulnerable to malaria. A pyronaridine-artesunate pediatric granule formulation is being developed for the treatment of uncomplicated Plasmodium falciparum malaria. METHODS: This phase III, multi-center, comparative, open-label, parallel-group, controlled clinical trial included patients aged ≤12 years, bodyweight ≥5 to <25 kg, with a reported history of fever at inclusion or in the previous 24 h and microscopically-confirmed uncomplicated P. falciparum malaria. Patients were randomized (2:1) to pyronaridine-artesunate granules (60/20 mg) once daily or artemether-lumefantrine crushed tablets (20/120 mg) twice daily, both dosed by bodyweight, orally (liquid suspension) for three days. RESULTS: Of 535 patients randomized, 355 received pyronaridine-artesunate and 180 received artemether-lumefantrine. Day-28 adequate clinical and parasitological response (ACPR), corrected for re-infection using polymerase chain reaction (PCR) genotyping (per-protocol population) was 97.1% (329/339; 95% CI 94.6, 98.6) for pyronaridine-artesunate; 98.8% (165/167; 95% CI 95.7, 99.9) for artemether-lumefantrine. The primary endpoint was achieved: pyronaridine-artesunate PCR-corrected day-28 ACPR was statistically significantly >90% (P < .0001). Pyronaridine-artesunate was non-inferior to artemether-lumefantrine: treatment difference -1.8% (95% CI -4.3 to 1.6). The incidence of drug-related adverse events was 37.2% (132/355) with pyronaridine-artesunate, 44.4% (80/180) with artemether-lumefantrine. Clinical biochemistry results showed similar mean changes versus baseline in the two treatment groups. From day 3 until study completion, one patient in each treatment group had peak alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN) and peak total bilirubin >2xULN (i.e. within the Hy's law definition). CONCLUSIONS: The pyronaridine-artesunate pediatric granule formulation was efficacious and was non-inferior to artemether-lumefantrine. The adverse event profile was similar for the two comparators. Pyronaridine-artesunate should be considered for inclusion in paediatric malaria treatment programmes. TRIAL REGISTRATION: ClinicalTrials.gov: identifier NCT00541385.

Efficacy and safety of a fixed-dose oral combination of pyronaridine-artesunate compared with artemether-lumefantrine in children and adults with uncomplicated Plasmodium falciparum malaria: a randomised non-inferiority trial.

BACKGROUND: There is a need for new artemisinin-based combination therapies that are convenient, effective, and safe. We compared the efficacy and safety of pyronaridine-artesunate with that of artemether-lumefantrine for treatment of uncomplicated P falciparum malaria. METHODS: This phase 3, parallel-group, double-blind, randomised, non-inferiority trial was undertaken in seven sites in Africa and three sites in southeast Asia. In a double-dummy design, patients aged 3-60 years with uncomplicated P falciparum malaria were randomly assigned in a 2:1 ratio to receive pyronaridine-artesunate once a day or artemether-lumefantrine twice a day, orally for 3 days, plus respective placebo. Randomisation was done by computer-generated randomisation sequence in blocks of nine by study centre. Intervention tablets contained 180 mg pyronaridine and 60 mg artesunate; control tablets contained 20 mg artemether and 120 mg lumefantrine. Both treatments were given according to bodyweight. The primary efficacy outcome was PCR-corrected adequate clinical and parasitological response (ACPR) rate at day 28 in the per-protocol population. Non-inferiority was shown if the lower limit of the two-sided 95% CI for the difference between groups was greater than -5%. This study is registered with ClinicalTrials.gov, number NCT00422084. FINDINGS: 1272 patients were randomly assigned to treatment (pyronaridine-artesunate, n=849; artemether-lumefantrine, n=423). The per-protocol population consisted of 784 patients in the pyronaridine-artesunate group and 386 patients in the artemether-lumefantrine group. PCR-corrected ACPR rate at day 28 was 99.5% (780 patients; 95% CI 98.7-99.9) in the pyronaridine-artesunate group and 99.2% (383 patients; 95% CI 97.7-99.8) in the artemether-lumefantrine group (treatment difference 0.3%, 95% CI -0.7 to 1.8; p=0.578). There were 509 (60.0%) adverse events in 849 patients assigned to pyronaridine-artesunate and 241 (57.0%) in 423 patients assigned to artemether-lumefantrine. The most frequent drug-related adverse event was eosinophilia (pyronaridine-artesunate, 53 events [6.2%]; artemether-lumefantrine 24 events [5.7%]). 21 (2.5%) patients in the pyronaridine-artesunate group and seven (1.7%) in the artemether-lumefantrine group discontinued study drugs or were withdrawn from the study. Mild and transient increases in alanine aminotransferase and aspartate aminotransferase concentrations were seen in the pyronaridine-artesunate group but not in the artemether-lumefantrine group. INTERPRETATION: Efficacy of pyronaridine-artesunate was non-inferior to that of artemether-lumefantrine for treatment of uncomplicated falciparum malaria. Pyronaridine-artesunate should be considered for inclusion in malaria treatment programmes. FUNDING: Shin Poong Pharmaceutical and the Medicines for Malaria Venture.

Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration.

Artesunate (AS) is a clinically versatile artemisinin derivative utilized for the treatment of mild to severe malaria infection. Given the therapeutic significance of AS and the necessity of appropriate AS dosing, substantial research has been performed investigating the pharmacokinetics of AS and its active metabolite dihydroartemisinin (DHA). In this article, a comprehensive review is presented of AS clinical pharmacokinetics following administration of AS by the intravenous (IV), intramuscular (IM), oral or rectal routes. Intravenous AS is associated with high initial AS concentrations which subsequently decline rapidly, with typical AS half-life estimates of less than 15 minutes. AS clearance and volume estimates average 2 - 3 L/kg/hr and 0.1 - 0.3 L/kg, respectively. DHA concentrations peak within 25 minutes post-dose, and DHA is eliminated with a half-life of 30 - 60 minutes. DHA clearance and volume average between 0.5 - 1.5 L/kg/hr and 0.5 - 1.0 L/kg, respectively. Compared to IV administration, IM administration produces lower peaks, longer half-life values, and higher volumes of distribution for AS, as well as delayed peaks for DHA; other parameters are generally similar due to the high bioavailability, assessed by exposure to DHA, associated with IM AS administration (> 86%). Similarly high bioavailability of DHA (> 80%) is associated with oral administration. Following oral AS, peak AS concentrations (Cmax) are achieved within one hour, and AS is eliminated with a half-life of 20 - 45 minutes. DHA Cmax values are observed within two hours post-dose; DHA half-life values average 0.5 - 1.5 hours. AUC values reported for AS are often substantially lower than those reported for DHA following oral AS administration. Rectal AS administration yields pharmacokinetic results similar to those obtained from oral administration, with the exceptions of delayed AS Cmax and longer AS half-life. Drug interaction studies conducted with oral AS suggest that AS does not appreciably alter the pharmacokinetics of atovaquone/proguanil, chlorproguanil/dapsone, or sulphadoxine/pyrimethamine, and mefloquine and pyronaridine do not alter the pharmacokinetics of DHA. Finally, there is evidence suggesting that the pharmacokinetics of AS and/or DHA following AS administration may be altered by pregnancy and by acute malaria infection, but further investigation would be required to define those alterations precisely.

Paraplegia after Open Repair of Suprarenal Abdominal Aortic Aneurysm.

Spinal cord ischemia after open repair of abdominal aortic aneurysm (AAA) is an unpredictable and devastating complication. We present a case report of a patient who developed paraplegia 6 hours after open repair of suprarenal AAA. A 74-yearold man presented with asymptomatic 5.5-cm suprarenal AAA, for which he underwent open repair under general anesthesia. The paraplegia was identified 6 hours after the operation. Postoperative magnetic resonance imaging showed T2 signal hyperintensity and swelling of the spinal cord, which were consistent findings with subacute spinal cord infarction. Although intravenous steroid was administered and lumbar cerebral spinal fluid drainage was instituted, his neurological outcome did not improve. He was discharged after vigorous rehabilitation but still has paraplegia and requires wheelchair for ambulation.

Clinical Manifestations of Symptomatic Spontaneous Dissection of the Celiac and Superior Mesenteric Arteries.

PURPOSE: Spontaneous isolated dissection of the celiac artery (SID-CA) and superior mesenteric artery (SID-SMA) are rare vascular diseases with similar presentation, yet comparative studies have not been reported. In this study, we compared their characteristics with the aim of providing insights into their etiology. MATERIALS AND METHODS: Patients diagnosed with symptomatic SID-CA and SIDSMA between July 2009 and December 2018 were included. Demographics, clinical presentation, radiologic findings, treatment strategies, and outcomes were analyzed. RESULTS: Twenty-one patients with SID-CA and 40 patients with SID-SMA were compared. Demographics and initial abdominal pain characteristics were similar, but pain severity was significantly higher and associated mean fasting time was significantly longer in patients with SID-CA than in those with SID-SMA (fasting time 3.2 vs 2.1 days, P=0.001). Most patients were successfully treated conservatively without recurrent pain or aneurysmal dilatation, but 33.3% patients with SID-CA and 17.5% with SID-SMA required endovascular intervention. More favorable remodeling in terms of dissection regression on follow-up computed tomography was found after stenting, where patients with SID-CA showed better remodeling than those with SID-SMA. The overall median follow-up period was 22-31 months, while for patients with stent insertion, it was 55-77 months, and no stent occlusions were found during this period. CONCLUSION: Patients with SID-CA presented with severer and longer-duration abdominal pain than those with SID-SMA. Stenting in both groups showed good long-term patency and favorable remodeling, with a higher regression rate for SIDCA. Based on our results, patients with SID-CA may benefit more from active endovascular intervention.

Clinical outcomes of the first 300 cases of kidney transplantation: a single-center retrospective cohort study.

Background: Kidney transplantation (KT) is regarded as the most effective treatment for end-stage renal disease. The annual number of KT cases in South Korea has increased rapidly as more centers are implementing a transplantation program. The objective of this study was to determine clinical outcomes of the first 300 consecutive cases of KT in a single center. Methods: Clinical data of 300 cases of KT at Seoul National University Bundang Hospital from January 2004 to March 2018 were obtained from a prospectively collected database and retrospectively reviewed. Results: The mean age of patients was 47.7±12.9 years, and 59% of patients were male. There were 225 living donors and 75 deceased donors. A total of 42 cases were from ABO-incompatible donors. During a mean follow-up of 68.6±43.5 months, 38 patients (12.7%) experienced rejection. The most common cause was acute T-cell mediated rejection (9.0%). Eighteen patients experienced graft loss. One-year and 5-year death-censored graft survival rates were 99% and 96.6%, respectively. One-year and 5-year patient survival rates were 98.3% and 96.6%, respectively. Multivariate analysis revealed that graft weight-to-recipient weight ratio and rejection were significant factors affecting graft survival. Conclusions: This single-center review demonstrates clinical outcomes comparable to other major centers. Such good outcomes were obtained by good patient selection, dedicated transplant physicians, and adequate use of immunosuppressive therapy.

Population pharmacokinetics of artesunate and dihydroartemisinin following single- and multiple-dosing of oral artesunate in healthy subjects.

BACKGROUND: The population pharmacokinetics of artesunate (AS) and its active metabolite dihydroartemisinin (DHA) were studied in healthy subjects receiving single- or multiple-dosing of AS orally either in combination with pyronaridine (PYR) or as a monotherapy with or without food. METHODS: Data from 118 concentration-time profiles arising from 91 healthy Korean subjects were pooled from four Phase I clinical studies. Subjects received 2-5 mg/kg of single- and multiple-dosing of oral AS either in combination with PYR or as a monotherapy with or without food. Plasma AS and DHA were measured simultaneously using a validated liquid chromatography- mass spectrometric method with a lower limit of quantification of 1 ng/mL for both AS and DHA. Nonlinear mixed-effect modelling was used to obtain the pharmacokinetic and variability (inter-individual and residual variability) parameter estimates. RESULTS: A novel parent-metabolite pharmacokinetic model consisting of a dosing compartment, a central compartment for AS, a central compartment and a peripheral compartment for DHA was developed. AS and DHA data were modelled simultaneously assuming stoichiometric conversion to DHA. AS was rapidly absorbed with a population estimate of absorption rate constant (Ka) of 3.85 h-1. The population estimates of apparent clearance (CL/F) and volume of distribution (V2/F) for AS were 1190 L/h with 36.2% inter-individual variability (IIV) and 1210 L with 57.4% IIV, respectively. For DHA, the population estimates of apparent clearance (CLM/F) and central volume of distribution (V3/F) were 93.7 L/h with 28% IIV and 97.1 L with 30% IIV, respectively. The population estimates of apparent inter-compartmental clearance (Q/F) and peripheral volume of distribution (V4/F) for DHA were 5.74 L/h and 18.5 L, respectively. Intake of high-fat and high-caloric meal prior to the drug administration resulted in 84% reduction in Ka. Body weight impacted CLM/F, such that a unit change in weight resulted in 1.9-unit change in CLM/F in the same direction. CONCLUSIONS: A novel simultaneous parent-metabolite pharmacokinetic model with good predictive power was developed to study the population pharmacokinetics of AS and DHA in healthy subjects following single- and multiple-dosing of AS with or without the presence of food. Food intake and weight were significant covariates for Ka and CLM/F, respectively.

Long-Term Symptoms of Mobile Phone Use on Mobile Phone Addiction and Depression Among Korean Adolescents.

This study aimed to compare the mean scores of mobile phone use, mobile phone addiction, and depressive symptoms at three-time points among Korean adolescents according to gender and to examine the differences in the long-term relationships among the three abovementioned variables between Korean boys and girls in a four-year period. Data for 1794 adolescents (897 boys and 897 girls) were obtained from three waves of the second panel of the Korean Children and Youth Panel Survey. Multigroup structural equation modeling was used for data analyses. The study findings showed that at each of the three-time points, Korean girls tended to use their mobile phones more frequently and were at a higher risk of mobile phone addiction and depressive symptoms than Korean boys. Significant changes were observed in the longitudinal relationships among phone use, mobile phone addiction, and depressive symptoms in Korean adolescents across time periods, but no gender differences were found in the strengths of these relationships. These findings contribute to expanding the knowledge base of mobile phone addiction and depressive symptoms among Korean adolescents.

Successful Treatment of Life-Threatening Small Bowel Bleeding With Thalidomide After Living Donor Kidney Transplantation: A Case Report.

Gastrointestinal bleeding after kidney transplantation is a complication that can occur from immunosuppressant use. We present a case of refractory small bowel bleeding treated successfully with thalidomide after multiple failed attempts of conventional treatment. A 65-year-old male patient with diabetic nephropathy underwent living donor kidney transplantation. The surgery was uneventful, however, he developed immunosuppressant-induced melena with unstable vital signs 11 days later. There were a total of 4 bleeding episodes until the 90th postoperative day, and he received a total of 290 units of red blood cell transfusion during this period. Endoscopic clipping, transarterial embolization, and 2 surgical interventions failed to stop the bleeding. A trial of thalidomide 100 mg per day finally stopped the bleeding and the patient was discharged on the 110th postoperative day with a functioning renal graft. This case shows that thalidomide can be a safe option to treat immunosuppressant-induced refractory gastrointestinal bleeding in the setting of kidney transplantation. Additionally, this is the first case that reports the survival of a renal graft after more than 3000 mL of transfusion.

Delayed appendectomy versus early appendectomy in the treatment of acute appendicitis: a retrospective study.

BACKGROUND: The controversy still exists about the timing of operation for appendicitis. The aim of this study was to compare the outcomes between early appendectomy and delayed appendectomy and assess the feasibility of delayed operation. METHODS: The medical records of patients with acute appendicitis who received operation between January 1, 2011 and December 31, 2011, were retrospectively reviewed. Outcome measures were white blood cell (WBC) count at postoperative first day, time to soft diet, complication rate, surgical site infection (SSI) rate, length of hospital stay, and readmission within 30 days. RESULTS: During the study period, a total of 478 patients underwent appendectomies, and 145 patients were excluded, leaving 333 who met inclusion criteria. Based on the time from arrival at hospital to incision, they were divided into two groups: 177 (53.2%) in group A and 156 (46.8%) in group B. There were no significant differences in preoperative demographics and clinical data between two groups. The mean WBC count at postoperative first day of group B were lower than that of group A (p = 0.0039). There were no significant differences in time to soft diet, length of postoperative hospital stay, complication rate, and readmission rate between two groups. SSI including intra-abdominal abscess was also shown no significant difference (Group A, 1.7% and Group B, 3.9%; p = 0.3143). CONCLUSIONS: This study revealed that delayed appendectomy was safe and feasible for adult patient although the clinical outcomes of delayed appendectomy were not superior to those of early appendectomy. We suggest that surgeons would decide the appropriate timing of appendectomy with consideration other situations such as available hospital resources.

Drug-drug interaction analysis of pyronaridine/artesunate and ritonavir in healthy volunteers.

A multiple dose, parallel group study was conducted to assess for a drug-drug interaction between the pyronaridine/artesunate (PA) combination antimalarial and ritonavir. Thirty-four healthy adults were randomized (1:1) to receive PA for 3 days or PA with ritonavir (100 mg twice daily for 17 days, PA administered on Days 8-10). Pharmacokinetic parameters for pyronaridine, artesunate, and its active metabolite dihydroartemisinin (DHA) were obtained after the last PA dose and for ritonavir on Days 1 and 10. Ritonavir coadministration did not markedly change pyronaridine pharmacokinetics but resulted in a 27% increase in artesunate area under the curve (AUC) and a 38% decrease in DHA AUC. Ritonavir exposure was increased 3.2-fold in the presence of PA. The only relevant safety observations were increases in liver enzymes, only reaching a clinically significant grade in the PA + ritonavir arm. It was concluded that coadministered ritonavir and PA interact to alter exposure to artesunate, DHA, and ritonavir itself.

Pyronaridine-artesunate versus chloroquine in patients with acute Plasmodium vivax malaria: a randomized, double-blind, non-inferiority trial.

BACKGROUND: New antimalarials are needed for P. vivax and P. falciparum malaria. This study compared the efficacy and safety of pyronaridine-artesunate with that of chloroquine for the treatment of uncomplicated P. vivax malaria. METHODS AND FINDINGS: This phase III randomized, double-blind, non-inferiority trial included five centers across Cambodia, Thailand, India, and Indonesia. In a double-dummy design, patients (aged >3-≤ 60 years) with microscopically confirmed P. vivax mono-infection were randomized (1:1) to receive pyronaridine-artesunate (target dose 7.2:2.4 mg/kg to 13.8:4.6 mg/kg) or chloroquine (standard dose) once daily for three days. Each treatment group included 228 randomized patients. Outcomes for the primary endpoint, Day-14 cure rate in the per-protocol population, were 99.5%, (217/218; 95%CI 97.5, 100) with pyronaridine-artesunate and 100% (209/209; 95%CI 98.3, 100) with chloroquine. Pyronaridine was non-inferior to chloroquine: treatment difference -0.5% (95%CI -2.6, 1.4), i.e., the lower limit of the 2-sided 95%CI for the treatment difference was greater than -10%. Pyronaridine-artesunate cure rates were non-inferior to chloroquine for Days 21, 28, 35 and 42. Parasite clearance time was shorter with pyronaridine-artesunate (median 23.0 h) versus chloroquine (32.0 h; p<0.0001), as was fever clearance time (median 15.9 h and 23.8 h, respectively; p = 0.0017). Kaplan-Meier estimates of post-baseline P. falciparum infection incidence until Day 42 were 2.5% with pyronaridine-artesunate, 6.1% with chloroquine (p = 0.048, log-rank test). Post-baseline P. vivax or P. falciparum infection incidence until Day 42 was 6.8% and 12.4%, respectively (p = 0.022, log rank test). There were no deaths. Adverse events occurred in 92/228 (40.4%) patients with pyronaridine-artesunate and 72/228 (31.6%) with chloroquine. Mild and transient increases in hepatic enzymes were observed for pyronaridine-artesunate. CONCLUSION: Pyronaridine-artesunate efficacy in acute uncomplicated P. vivax malaria was at least that of chloroquine. As pyronaridine-artesunate is also efficacious against P. falciparum malaria, this combination has potential utility as a global antimalarial drug. TRIAL REGISTRATION: Clinicaltrials.gov NCT00440999.