Safety and efficacy of re-treatments with pyronaridine-artesunate in African patients with malaria: a substudy of the WANECAM randomised trial.

BACKGROUND: Sparse data on the safety of pyronaridine-artesunate after repeated treatment of malaria episodes restrict its clinical use. We therefore compared the safety of pyronaridine-artesunate after treatment of the first episode of malaria versus re-treatment in a substudy analysis. METHODS: This planned substudy analysis of the randomised, open-label West African Network for Clinical Trials of Antimalarial Drugs (WANECAM) phase 3b/4 trial was done at six health facilities in Mali, Burkina Faso, and Guinea in patients (aged ≥6 months and bodyweight ≥5 kg) with uncomplicated microscopically confirmed Plasmodium spp malaria (parasite density <200 000 per µL blood) and fever or history of fever. The primary safety endpoint was incidence of hepatotoxicity: alanine aminotransferase of greater than five times the upper limit of normal (ULN) or Hy's criteria (alanine aminotransferase or aspartate aminotransferase greater than three times the ULN and total bilirubin more than twice the ULN) after treatment of the first episode of malaria and re-treatment (≥28 days after first treatment) with pyronaridine-artesunate. Pyronaridine-artesunate efficacy was compared with artemether-lumefantrine with the adequate clinical and parasitological response (ACPR) in an intention-to-treat analysis. WANECAM is registered with PACTR.org, number PACTR201105000286876. FINDINGS: Following first treatment, 13 (1%) of 996 patients had hepatotoxicity (including one [<1%] possible Hy's law case) versus two (1%) of 311 patients on re-treatment (neither a Hy's law case). No evidence was found that pyronaridine-artesunate re-treatment increased safety risk based on laboratory values, reported adverse event frequencies, or electrocardiograph findings. For all first treatment or re-treatment episodes, pyronaridine-artesunate (n=673) day 28 crude ACPR was 92·7% (95% CI 91·0-94·3) versus 80·4% (77·8-83·0) for artemether-lumefantrine (n=671). After exclusion of patients with PCR-confirmed new infections, ACPR was similar on treatment and re-treatment and greater than 95% at day 28 and greater than 91% at day 42 in both treatment groups. INTERPRETATION: The findings that pyronaridine-artesunate safety and efficacy were similar on first malaria treatment versus re-treatment of subsequent episodes lend support for the wider access to pyronaridine-artesunate as an alternative artemisinin-based combination treatment for malaria in sub-Saharan Africa. FUNDING: European and Developing Countries Clinical Trial Partnership, Medicines for Malaria Venture (Geneva, Switzerland), UK Medical Research Council, Swedish International Development Cooperation Agency, German Ministry for Education and Research, University Claude Bernard (Lyon, France), Malaria Research and Training Centre (Bamako, Mali), Centre National de Recherche et de Formation sur le Paludisme (Burkina Faso), Institut de Recherche en Sciences de la Santé (Bobo-Dioulasso, Burkina Faso), and Centre National de Formation et de Recherche en Santé Rurale (Republic of Guinea).

A pilot study of L-methionine for the treatment of AIDS-associated myelopathy.

The pathogenesis of AIDS-associated vacuolar myelopathy (VM) may be related to abnormality of transmethylation mechanisms in the nervous system. To evaluate the safety and potential efficacy of the methyl-group donor L-methionine in AIDS-associated VM, we conducted a pilot clinical trial in 12 patients with VM. Seven of the nine patients who completed the study had clinical and electrophysiologic improvement. Controlled studies may be indicated to assess the efficacy and safety of L-methionine in AIDS-associated VM.

Chromosomal abnormalities in the first and second polar body.

Aneuploidy free oocytes may be pre-selected by testing the first and second polar bodies removed from oocytes following their maturation and fertilization. We present here our experience on the application of the method in IVF cycles from patients of advanced maternal age. Overall, 5590 oocytes were obtained from 917 cycles and tested by polar body sampling and fluorescent in situ hybridization (FISH) analysis using specific probes for chromosomes 13,16,18,21 and 22. FISH results were available in 4599 (82.2%) of 5590 oocytes studied, from which 2077(45.2%) were with aneuploidies. Thirty six point one percent of aneuploidies were of the first meiotic origin, and 29.3% of the second meiotic origin. Most errors in the first meiotic division were represented by chromatid errors. The transfer of embryos deriving from 2014 of 2520 aneuploidy free oocytes in 821 treatment cycles resulted in 182 (22.2%) clinical pregnancies and 140 healthy children born after confirmation of the polar body diagnosis. Polar body testing of oocytes provides an approach for pre-selection of aneuploidy free embryos, improving pregnancy rate in IVF patents of advanced maternal age.

Pragmatics in understanding what is said.

A central claim in cognitive science is that speakers often say things which underdetermine what they imply by their use of utterances in context. For example, in uttering Jane has three children a speaker might only say that Jane has at least three children and may have more than three, but the speaker's utterance implicates that Jane has exactly three children. Many scholars following Grice have argued from such observations that pragmatics plays only a small part in determining what speakers say, as opposed to what they conversationally imply or implicate. We examined people's intuitions about the distinction between what speakers say, or what is said, and what they implicate by different indicative utterances, such as Jane has three children. The data from four experiments demonstrate that people do not equate a minimal meaning (i.e., Jane has at least three children and may have more than three) with what a speaker says, but assume that enriched pragmatics plays a significant role in determining what is said (i.e., Jane has exactly three children). People further recognize a distinction between what speakers say, or what is said, and what speakers implicate in particular contexts (e.g., Jane is married). These data lend support to theories of utterance interpretation in cognitive science that pragmatics strongly influences people's understanding of what speakers both say and communicate.

A simpler technique for reduction of uterine septum.

Hysteroscopic resection of the uterine septum is currently the accepted technique for dealing with this congenital uterine abnormality. Its advantages over the transabdominal approach are: it can be performed on an outpatient basis, it requires minimal recovery time, and it does not commit the patient to a subsequent cesarean section. This communication reports on a new transcervical approach that does not require the use of a hysteroscope. Thirty-four patients have now undergone resection of uterine septae using this technique. The results have been consistently good, requiring a short operative time and minimal instrumentation. We have experienced no complications.

Prepregnancy testing for single-gene disorders by polar body analysis.

Preventive measures for single-gene disorders are currently based on carrier screening in pregnancy and prenatal diagnosis. Although this has been extremely effective for preventing new cases of common inherited conditions, the major limitation is still termination of 25% of wanted pregnancies following detection of affected fetuses. To overcome this important problem, we developed a method for prepregnancy genetic testing that involves DNA analysis of the first and second polar bodies, which are extruded during maturation and fertilization of oocytes. We offered this option to 28 couples at risk for having children with single-gene disorders. Fifty clinical cycles were performed from these patients for the following conditions: 20 for cystic fibrosis, 18 for thalassemia, 6 for sickle cell disease, 2 each for Gaucher disease and LCHAD (long-chain 3-hydroxyacyl-COA dehydrogenase deficiency), and 1 each for hemophilia B and phenylketonuria. Oocytes obtained from these patients using in vitro fertilization procedures (IVF) were tested by a sequential multiplex nested PCR analysis of the first and second polar body to detect the gene involved simultaneously with linked polymorphic markers. A total of 191 of 399 oocytes with predicted genotype were mutation free and preselected for fertilization and transfer. In all but three cycles, one to three unaffected embryos with predicted unaffected genotypes were transferred, resulting in 20 pregnancies, from which 19 healthy children have been born. The follow-up analysis of embryos resulting from oocytes with predicted affected genotype, confirmed the diagnosis in 97% of cases, demonstrating the reliability of prepregnancy diagnosis of single-gene defects by polar body analysis.

Prepregnancy genetic testing for age-related aneuploidies by polar body analysis.

Current practice for prevention of chromosomal aneuploidies involves prenatal screening and termination of pregnancy, a procedure that is not universally acceptable. We introduced prepregnancy genetic testing by sampling and fluorescence in situ hybridization (FISH) analysis of the first and second polar body (PB), to avoid fertilization and transfer of embryos resulting from aneuploid oocytes. In 395 in vitro fertilization (IVF) patients of advanced maternal age, the first and second PBs were removed following their extrusion from oocytes and studied by FISH, using probes specific for chromosomes 13, 18, and 21, to detect and avoid the transfer of oocytes with common aneuploidies. Overall, 3,651 oocytes obtained from 598 IVF cycles were available for FISH analysis, with 2,952 showing interpretable FISH results (80.9%). The analysis revealed 1,271 (43.1%) oocytes with aneuploidy, which were excluded from transfer and subjected to follow-up FISH analysis to confirm PB diagnosis in the cleavage or blastocyst stage embryos. Only embryos originating from 1,681 aneuploidy-free oocytes were transferred back to patients, resulting in 119 pregnancies overall, from which 78 healthy children have already been born, 35 were spontaneously aborted, and 16 are ongoing, after confirming PB diagnosis by prenatal diagnosis. The results demonstrate that PB-based preimplantation diagnosis may be used for prepregnancy screening in women with age-related risk for common aneuploidies.

The Hemopump--a new cardiac prothesis device.

A unique cardiac prothesis device is currently undergoing clinical trials. Called the Hemopump, this device is a radical new design of a temporary left ventricular assist blood pump. It uses a miniature (7 mm diameter) axial flow pump placed transvalvular across the aortic valve which pumps blood from the left ventricle to the aorta. Mechanical power from an external motor is transmitted percutaneously to the pump by a flexible cable contained within a catheter-like sheath. This arrangement allows the pump to be placed through a femoral artery cutdown without requiring major surgery. Development of the Hemopump concept presented significant challenges in pump hydraulic design, bearing, and seal design, as well as materials selection and miniature parts fabrication. Clinical trial results thus far indicate these challenges have been well met and that the Hemopump has the potential to become a widely used safe and effective clinical device.

Correlates of psychosocial adjustment among young adults with cystic fibrosis.

Young adults with cystic fibrosis (CF) (n = 73) were found to have age-adequate psychological functioning. Psychological adjustment, as measured by the Psychological Screening Inventory (PSI) and the Tennessee Self-Concept Inventory (TSCI), correlated with coping style as measured by the Repression-Sensitization (R-S) scale. A repressive or avoidant coping style was associated with higher self-esteem, lower alienation and discomfort, and greater social activity, but not with employment status or school attendance. Severely ill patients were less likely to be employed or in school, and showed higher levels of psychological discomfort. Physicians' ratings of coping effectiveness were positively related to a repressive illness-related coping style. Prospective assessment of psychological functioning would yield useful information concerning the coping strategies used by young adults with CF to ameliorate the psychological distress associated with physical deterioration.

Investigation of a cluster of cutaneous aspergillosis in a neonatal intensive care unit.

Between December 2007 and July 2008, three neonates in a neonatal intensive care unit (NICU) in Salford, UK, were diagnosed with primary cutaneous aspergillosis (PCA) due to Aspergillus fumigatus. The first PCA case, in December 2007, developed multi-organ failure leading to death within a short time frame: the other two cases survived after treatment with intravenous antifungal therapy followed by oral posaconazole. Air, surface, and water samples were collected within the NICU and from the incubators that were occupied by the neonates. All recovered fungal isolates were confirmed as A. fumigatus by sequencing the beta-tubulin region. Microsatellite strain typing demonstrated genotypically related A. fumigatus isolates from the neonates and the humidity chambers (HCs) of the neonates' incubators, suggesting that the source of the infection may have been the HCs/incubators used in the NICU. Aspergillus strain typing may be a useful tool in clinical outbreak settings to help understand the source of exposure and to design targeted environmental interventions to prevent future infections.

The effect of dehydroepiandrosterone sulfate on de novo and low-density lipoprotein-stimulated progesterone secretion by human choriocarcinoma JEG-3 cells.

It has been suggested that fetal adrenal steroids affect the secretion of progesterone by the human trophoblast and decrease the progesterone/estrogen secretory ratio at the time of parturition. In the present study, cultured human choriocarcinoma JEG-3 cells were used as an experimental model in order to examine the effect of dehydroepiandrosterone sulfate on both de novo and low-density lipoprotein-stimulated progesterone secretion. In serum-free and cholesterol-free Dulbecco's modified Eagle's medium, JEG-3 cell cultures demonstrated a significant secretion of both pregnenolone and progesterone. A 200% to 300% increase in pregnenolone and progesterone secretion was achieved by physiologic low-density lipoprotein concentrations added to Dulbecco's modified Eagle's medium while androgens and estrogens remained undetectable. Dehydroepiandrosterone sulfate added to Dulbecco's modified Eagle's medium was actively converted into C-19 and C-18 steroids but had no significant effect (up to 20 micrograms/ml) on basal (de novo) progesterone secretion. In contrast, the addition of dehydroepiandrosterone sulfate (1 to 5 micrograms/ml) to cultures grown in Dulbecco's modified Eagle's medium plus low-density lipoprotein induced a dose-related inhibition of progesterone and a return of that secretion to basal levels.

Classification of threatened premature labor related to treatment with a prostaglandin inhibitor: indomethacin.

68 patients complaining of premature uterine contractions were treated with a prostaglandin synthetase inhibitor--indomethacin. This agent had a marked effect on uterine contractions suppressing them completely after 1--8 h from the administration of the drug. Classificaiton of the premature contractions according to a scoring system method is analyzed in this study. The score classified the patients into three groups and enabled us to treat them with a correct dosage and period according to the clinical findings at admission of the patients. Indomethacin treatment was effective in all the 68 patients. The drug was well tolerated by all the patients with minimal side effects. The outcome of the newborns was satisfactory, and laboratory tests on various systems of the pregnant women and newborns were normal during and after treatment with indomethacin.

Perforated gastric ulcer complicating corticosteroid therapy in acute rheumatic fever.

We report an 11-year-old boy with acute rheumatic fever who presented with gastric perforation while treated with corticosteroids (CS). He had been treated initially with acetylsalicylic acid for 11 days, CS replaced the treatment with acetylsalicylic acid due to deterioration of carditis. The possible pathogenesis is discussed.

In vivo evaluation of a peripheral vascular access axial flow blood pump.

More than 80 acute and chronic calf in vivo studies were utilized to develop a 3 L/min axial flow blood pump designed for intraarterial ventricular assist. The 7 mm diameter transvalvular inlet cannula of the cable driven pump receives blood from the left ventricle. The pump then discharges blood into the descending aorta. In the calf, the pump was introduced into the renal aorta. Safety and effectiveness of the device were demonstrated in three control and 21 implanted animals. Blood chemistry results showed an average plasma free hemoglobin of 3 mg/dl for control and 6.7 mg/dl for implanted animals. Platelets were 1.04 X 10(6) and 0.65 X 10(6), respectively, for control and implanted animals. Fibrinogen, BUN, creatinine, and bilirubin were essentially the same for both groups of animals. The hardware was typically free of deposits, and histopathologic examination revealed minimal injury to intracardiac structures, aortic valve leaflets, and aortic intima. The data indicates that the device may provide full support for a failing left ventricle with minimal trauma or risk.

Development of compact thermal and electrical energy converters left heart assist systems.

The thermal converter for left heart assist systems consists of an engine which converts thermal energy to a flow of pressurized helium and a helium powered actuator/controller which powers and controls a PVAD pusher plate blood pump. The 0.43 L, 0.94 kg engine requires 20 watts of thermal input. In vitro and in vivo testing have demonstrated that the system synchronizes and provides left ventricle relief from 60 to 150 beats/min. The concepts potential for long life is based on: the inert environment for all internal components; the hermetic sealing capability resulting from a linear magnetic coupling blood pump drive; fluid control; and titanium external metal surfaces. Endurance testing has demonstrated that the converter shows promise of providing a high reliability 10 yr life. Many wear and fatigue sensitive components have demonstrated the 10 yr capability during accelerated life testing.

The Highmark Pegasus Project report: characteristics of highly successful health plans.

The Highmark Blue Cross/Blue Shield Pegasus Project was created in the fall of 1996 to benchmark best practices at health plans around the United States through extensive interviews, literature searches, and other measures. Characteristics of highly successful health plans across a number of major categories are summarized in the final recommendations presented by this report.