Contemporary fluid management, humidity, and patent ductus arteriosus management strategy for premature infants among 336 hospitals in Asia.

Objectives: The management of patent ductus arteriosus (PDA) is a critical concern in premature infants, and different hospitals may have varying treatment policies, fluid management strategies, and incubator humidity. The Asian Neonatal Network Collaboration (AsianNeo) collected data on prematurity care details from hospitals across Asian countries. The aim of this study was to provide a survey of the current practices in the management of PDA in premature infants in Asian countries. Methods: AsianNeo performed a cross-sectional international questionnaire survey in 2022 to assess the human and physical resources of hospitals and clinical management of very preterm infants. The survey covered various aspects of hospitals resources and clinical management, and data were collected from 337 hospitals across Asia. The data collected were used to compare hospitals resources and clinical management of preterm infants between areas and economic status. Results: The policy of PDA management for preterm infants varied across Asian countries in AsianNeo. Hospitals in Northeast Asia were more likely to perform PDA ligation (p < 0.001) than hospitals in Southeast Asia. Hospitals in Northeast Asia had stricter fluid restrictions in the first 24 h after birth for infants born at <29 weeks gestation (p < 0.001) and on day 14 after birth for infants born at <29 weeks gestation (p < 0.001) compared to hospitals in Southeast Asia. Hospitals in Northeast Asia also had a more humidified environment for infants born between 24 weeks gestation and 25 weeks gestation in the first 72 h after birth (p < 0.001). A logistic regression model predicted that hospitals were more likely to perform PDA ligation for PDA when the hospitals had a stricter fluid planning on day 14 after birth [Odds ratio (OR) of 1.70, p = 0.048], more incubator humidity settings (<80% vs. 80%-89%, OR of 3.35, p = 0.012 and <80% vs. 90%-100%, OR of 5.31, p < 0.001). Conclusions: In advanced economies and Northeast Asia, neonatologists tend to adopt a more conservative approach towards fluid management, maintain higher incubator humidity settings and inclined to perform surgical ligation for PDA.

Variations in medical practice of retinopathy of prematurity among 8 Asian countries from an international survey.

Advances in perinatal care have led to the increased survival of preterm infants with subsequent neonatal morbidities, such as retinopathy of prematurity (ROP). This study aims to compare the differences of neonatal healthcare systems, resources, and clinical practice concerning ROP in Asia with review of current literature. An on-line survey at the institutional level was sent to the directors of 336 neonatal intensive care units (NICU) in 8 collaborating national neonatal networks through the Asian Neonatal Network Collaboration (AsianNeo). ROP screening was performed in infants born at < 34 weeks in Indonesia and Japan. In South Korea, Malaysia, and Taiwan, most screened for ROP in infants born at < 32 weeks. In all networks, majority of NICUs conducted ROP screening to infants with birth weight < 1500 g. In most NICU's in-hospital ophthalmologists performed indirect ophthalmoscopy and some were supplemented with digital imaging. Both laser photocoagulation and anti-vascular endothelial growth factor injection are performed for treatment and, vitreous surgeries are conducted less frequently in all countries. Despite limited information collected by the survey, this first study to compare ROP practices implemented in eight Asian countries through AsianNeo will enable an understanding of the differences and facilitate quality improvement by sharing better practices.

A randomized, multicenter, placebo-controlled clinical trial of racotumomab-alum vaccine as switch maintenance therapy in advanced non-small cell lung cancer patients.

PURPOSE: Racotumomab-alum is an anti-idiotype vaccine targeting the NeuGcGM3 tumor-associated ganglioside. This clinical trial was conducted to provide a preliminary estimate of efficacy and safety of racotumomab as switch maintenance for patients with advanced non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Patients with stage IIIb/IV NSCLC who have at least stable disease after first-line chemotherapy were randomized 1:1 to racotumomab-alum (5 immunizations every 2 weeks and re-immunizations every 4 weeks) or placebo. Treatment was administered beyond progressive disease, until severe performance status worsening or toxicity. At progression, only five patients per group received further anticancer therapy. The primary endpoint was overall survival (OS). RESULTS: One-hundred and seventy-six patients were randomized to racotumomab-alum (n = 87) and placebo (n = 89). Median OS was 8.23 and 6.80 months, respectively [HR, 0.63; 95% confidence interval (CI), 0.46-0.87; P = 0.004]. Median progression-free survival (PFS) in vaccinated patients was 5.33 versus 3.90 months for placebo (HR, 0.73; 95% CI 0.53-0.99; P = 0.039). The most common adverse events in the racotumomab-alum arm were burning and pain at the injection site, bone pain, and asthenia. A high antibody response of IgM and IgG isotype against the NeuGcGM3 ganglioside was obtained. Hyperimmune sera were able to specifically recognize and kill the NeuGcGM3-expressing L1210 cell line. Patients who developed anti-NeuGcGM3 antibodies capable to bind and kill ≥30% L1210 cells showed longer median survival times. CONCLUSIONS: Switch maintenance with racotumomab-alum is an effective and a well-tolerated treatment option for patients with advanced NSCLC.

Characteristics of ectopic parathyroid glands in 145 cases of primary hyperparathyroidism.

OBJECTIVE: To determine the prevalence of primary hyperparathyroidism (PHPT) arising from ectopic parathyroid glands, to analyze the clinical, biochemical, and anatomic characteristics of such cases, and to compare these characteristics with those found in PHPT associated with orthotopic parathyroid glands. METHODS: We conducted a retrospective study of cases of PHPT evaluated and treated at a referral center. Differences between patients with orthotopic and ectopic parathyroid glands were analyzed statistically. RESULTS: During a recent 5-year period at our institution, 145 cases of PHPT were treated operatively by 3 experienced surgeons. An ectopic parathyroid location was detected in 13 cases (9%). Of the 13 ectopic glands, 4 (31%) were at the tracheoesophageal groove, 4 (31%) were intrathymic, 2 (15%) were intrathyroidal, and 1 each was located in the aortopulmonary window, the anterior (nonthymic) mediastinum, and the submaxillary region. Patients with PHPT attributable to ectopic adenomas had significantly higher serum calcium levels (12.6 ± 0.9 mg/dL versus 11.4 ± 1.2 mg/dL; P = .05) and larger tumors (25 ± 6.1 mm versus 19 ± 7.6 mm; P = .05) than did patients with orthotopic parathyroid glands. Moreover, hyperparathyroidism- related bone disease was significantly more frequent in patients with abnormal ectopic parathyroid glands than in those with orthotopic parathyroid glands (23% versus 1.5%, respectively; P = .04). CONCLUSION: In 9% of all cases of PHPT in our study, the condition was associated with ectopically located parathyroid glands. Such cases are usually characterized by larger parathyroid glands, higher serum calcium levels, and a higher frequency of severe bone disease.

1E10 anti-idiotype vaccine in non-small cell lung cancer: experience in stage IIIb/IV patients.

Conventional treatment of non-small cell lung cancer (NSCLC) has apparently reached a plateau of effectiveness in improving the survival of the patients. For that reason the search for new therapeutic strategies in this type of tumor is justified. 1E10 is an anti-idiotype murine monoclonal antibody (Ab2 MAb) specific to P3 Ab1 MAb, which reacts with NeuGc-containing gangliosides, sulfatides and with antigens expressed in some tumors, including those from the lung. We report the treatment with aluminum hydroxide-precipitated 1E10 MAb of 34 stage IIIb and 37 stage IV NSCLC patients. These patients were treated with the anti-idiotype vaccine, after received standard chemotherapy and radiotherapy, in a compassionate-use basis study. Patients received five bi-weekly injections of 1 mg of 1E10/Alum, other 10 doses at 28-day intervals and later the patients who maintained a good performance status continued to be immunized at this same time interval. No evidence of unexpected or serious adverse effects was reported. The median survival time of the 56 patients who entered the study with partial response or disease stabilization and with a PS 1 after the first line of chemo/radiotherapy, was 11.50 months from starting vaccination. In contrast, the median survival time calculated for patients who started vaccination with progressive disease and/or a PS2 was 6.50 months.

Tetrahydrobenzothiophene inhibitors of hepatitis C virus NS5B polymerase.

A novel series of selective HCV NS5B RNA dependent RNA polymerase inhibitors has been disclosed. These compounds contain an appropriately substituted tetrahydrobenzothiophene scaffold. This communication will detail the SAR and activities of this series.

Characterization of gentamicin-resistant Mycoplasma hyorhinis.

A study was conducted to determine if a gentamicin-resistant strain of mycoplasma could be developed for use in validating current mycoplasma detection methods for biologic product harvest cell culture fluid (CCF) containing gentamicin. A strain of gentamicin-resistant Mycoplasma hyorhinis was isolated and characterized. The study showed that this organism was similar to the wild-type strain in all ways examined except gentamicin resistance. Both strains of mycoplasma (the gentamicin resistant and the wild-type) exhibited comparable growth patterns and showed 100% homology based on DNA sequencing and analysis of a 464-bp PCR product. Also, analysis using species-specific antisera identified both strains as M. hyorhinis. Two commonly used lot release mycoplasma detection methods (culture and DNAF) consistently detected mycoplasmas in spiked biologic product harvest CCF containing gentamicin but not in unspiked samples. This study demonstrates the first isolation and characterization of a gentamicin-resistant M. hyorhinis that can be used to validate mycoplasma detection methods for biologic product harvest CCF containing gentamicin.

Insulin revisited.

Injury and critical illness are characterised by hyperglycaemia, high free fatty acids and high net protein catabolism, due partly to suppression of insulin secretion in the shock phase and insulin resistance in the flow phase of injury, accompanied by high levels of cytokines and the catabolic hormones cortisol, glucagon and catecholamines. Pre-operative carbohydrate loading reduces post-operative insulin resistance and its consequences. Insulin has been shown to reduce the catabolic response as well as controlling hyperglycaemia. In contrast to its sodium retaining properties in normal, obese and diabetic subjects, insulin-glucose-potassium therapy may induce a sodium diuresis in catabolic patients with salt and water overload and in patients with congestive heart failure in whom haemodynamic improvement has also been observed. Diabetic patients with myocardial infarction and cardiac surgery also benefit from insulin treatment. Recent studies have described positive effects on clinical outcome in critical illness. Whether this is due simply to maintenance of euglycaemia or to the other effects of insulin remains to be determined.

Discovery of 1-[3-(aminomethyl)phenyl]-N-3-fluoro-2'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa.

Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as the point of convergence of the intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va and Ca2+ on the phospholipid surface of platelets or endothelial cells, factor Xa forms the prothrombinase complex, which is responsible for the proteolysis of prothrombin to catalytically active thrombin. Thrombin, in turn, catalyzes the cleavage of fibrinogen to fibrin, thus initiating a process that ultimately leads to clot formation. Recently, we reported on a series of isoxazoline and isoxazole monobasic noncovalent inhibitors of factor Xa which show good potency in animal models of thrombosis. In this paper, we wish to report on the optimization of the heterocyclic core, which ultimately led to the discovery of a novel pyrazole SN429 (2b; fXa K(i) = 13 pM). We also report on our efforts to improve the oral bioavailability and pharmacokinetic profile of this series while maintaining subnanomolar potency and in vitro selectivity. This was achieved by replacing the highly basic benzamidine P1 with a less basic benzylamine moiety. Further optimization of the pyrazole core substitution and the biphenyl P4 culminated in the discovery of DPC423 (17h), a highly potent, selective, and orally active factor Xa inhibitor which was chosen for clinical development.

Design and synthesis of potent and selective 5,6-fused heterocyclic thrombin inhibitors.

Thrombin, a serine protease, plays a central role in the initiation of thrombotic events. We report the design, synthesis, and antithrombotic efficacy of XU817 (7), a nonpeptide 5-(amidino) indole thrombin inhibitor. Utilizing the co-crystal structure of XU817 bound in the active site of thrombin we were able to synthesize analogs with enhanced thrombin affinity.

Arabinogalactan-coated superparamagnetic iron oxide: effect of particle size in liver MRI.

OBJECTIVE: We evaluated the effect of particle size on MR contrast-enhancing properties of arabinogalactan-coated superparamagnetic iron oxide (AG-SPIO) in tumor-bearing rats. MATERIALS AND METHODS: T2*-weighted gradient-recalled echo MR studies were performed on rats with surgically implanted liver tumors before and after AG-SPIO administration. Contrast-to-noise ratio (CNR) and percent contrast enhancement (PCE) were calculated for animals given small (15.7 +/- 9.5 nm: n = 6), medium (49.1 +/- 19.7 nm; n = 4), and large (86.9 +/- 27.5 nm; n = 4) particles intravenously (10 mumol Fe/kg). RESULTS: Postcontrast CNRs were 15.8 +/- 6.9, 8.9 +/- 4.1, and 10.0 +/- 1.8 for small, medium, and large particle groups, respectively. The PCE was -60.0 +/- 3.3, -75.5 +/- 7.9, and -80.5 +/- 1.2%. There was a significant difference in preversus postcontrast CNR for all particle sizes (p < 0.001) and in PCE for small particles as compared with the two larger sizes (p < 0.001). There was no between-group statistical difference in postcontrast CNR for any particle size. CONCLUSION: Larger AG-SPIO particles slightly improve liver contrast enhancement, but have no significant effect on hepatic lesion detection as assessed by CNR.

Preclinical evaluation of manganese carbonate particles for magnetic resonance imaging of the liver.

RATIONALE AND OBJECTIVES: We characterized the physical, biological, and imaging properties of a manganese (Mn) carbonate particle suspension, a contrast agent for hepatic magnetic resonance (MR) imaging. METHODS: Mn carbonate suspensions were produced by controlled precipitation and characterized using light microscopy, transmission electron microscopy, and in vitro relaxivity studies. Efficacy of the agent was studied in normal and tumor-bearing rats using T1-weighted MR imaging. RESULTS: Following intravenous injection of Mn carbonate particles at doses ranging from 10 to 100 mumol Mn/kg, peak hepatic contrast enhancement of approximately 35% occurred from about 125 min until the termination of the MR imaging studies that varied from 125 to 305 min. Lesion conspicuity was increased because of relative intensity differences between normal liver and tumor. Data also showed that Mn carbonate particles dissolved on delivery to the liver, allowing Mn to interact with intrahepatic macromolecular complexes to provide positive contrast enhancement. CONCLUSION: Mn carbonate particles produce significant and sustained hepatic enhancement and should improve detection of small or isointense liver lesions.

Is there a role for diskography in the era of magnetic resonance imaging? Prospective correlation and quantitative analysis of computed tomography-diskography, magnetic resonance imaging, and surgical findings.

We herein report the results of a prospective study to define the role of diskography in the diagnosis of low back pain in an emerging era of magnetic resonance imaging (MRI). The study involved 32 patients (78 disks) with a clinical diagnosis of lumbar disk herniation; all were studied by computed tomography-diskography (CT-D), and 25 (51 disks) were also examined using MRI. The disks were graded on these studies according to a staging scheme modified from Modic. Ten of the patients (13 disks) having both CT-D and MRI underwent exploratory surgery, and the staging at surgery served as the standard against which the evaluative studies were judged. Surgical staging was compatible with the CT-D and MRI results in five disks, while in another five disks it was compatible only with the CT-D results. In the remaining three disks, both CT-D and MRI misidentified the stages. In six disks, CT-D more accurately defined the stage of disease than did MRI, whereas MRI was more precise than CT-D in only one disk. While having documented the value of CT-D as a source of information, particularly when surgery is contemplated, and as an effective means of staging disk herniation, we recommend MRI as the ideal screening test for lumbar radiculopathy and low back pain, reserving diskography for problematic cases.

Anatomic variation of the corpus callosum in persons with gender dysphoria.

Previous postmortem anatomical studies have demonstrated differences between male and female in the size and shape of the splenium of the corpus callosum. The current study using the magnetic resonance imager compares the corpus callosum in 20 transsexuals and 40 controls to determine if the anatomic variance is related to anatomic sex or gender identity. No statistical differences were found in the cross-sectional areas of the entire corpus callosum, regardless of genetic sex or gender. However, the genetic males did have a larger whole-brain cross-sectional area. Also, even though there was a wide range of differences in shape and size in the splenium, the study found no significant differences between the sexes or between transsexual patients of either sex and the controls.

T-gamma-lymphoproliferative disorder arising in a background of autoimmune disease and terminating in plasma cell dyscrasia with primary amyloidosis.

T-gamma-lymphoproliferative disorder, a syndrome of T-cell lymphocytosis with neutropenia has been described in patients with various autoimmune disorders, especially rheumatoid arthritis. We report a case of T-gamma-lymphoproliferative disorder occurring in a 42-year-old white woman with a long history of dermatitis herpetiformis and subsequent development of Coomb's positive autoimmune hemolytic anemia and polymyositis. The peripheral blood lymphocytes showed the T-suppressor cell phenotype (CD2-, CD3-, CD8-, and CD4-). DNA analysis of the peripheral blood lymphocytes revealed a T-cell receptor beta-chain gene rearrangement and an immunoglobulin heavy-chain gene rearrangement. The patient's course was marked by numerous bouts of infection. The unique factor in this patient was the development of a plasma cell dyscrasia and amyloidosis prior to death.

Magnetic resonance imaging and neuropsychological findings in human immunodeficiency virus infection.

Neurobehavioral functioning and magnetic resonance imaging (MRI) were investigated in 25 patients with various Centers for Disease Control (CDC) stages of human immunodeficiency virus (HIV) infection and in a control group of seven normal subjects. Unequivocal slowing of information processing speed and cerebral atrophy were related to the stage of HIV infection, with patients in CDC group IV exhibiting the most abnormal findings. Slowing of response speed was directly related to the severity of cerebral atrophy.

Localization of auditory response sources using magnetoencephalography and magnetic resonance imaging.

Magnetoencephalography offers the possibility of localizing accurately and noninvasively the source of intracranial currents associated with normal and abnormal brain activity. The purpose of this study was to assess the validity and across-subject reliability of localization of cortical sources responding to ipsilateral and contralateral auditory stimulation. Magnetic evoked fields to both stimulation conditions were measured in eight consecutive normal subjects, and the cortical sources of these fields were estimated on the basis of these measurements. Subsequent projection of the source location coordinates onto magnetic resonance images showed that in all subjects the sources were accurately estimated to fall in the vicinity of the auditory cortex and that two separate sources may account for the response to ipsilateral and contralateral stimulation.