Single Intrauterine Death in Twins: The Importance of Fetal Order.

Perinatal mortality is higher in twins. Effects of twin order have not previously been studied in the context of single fetal demise. Our objective was to determine whether death of the fetus more proximal to the cervix will result in worse perinatal outcomes. Our population included multiple pregnancies with two viable fetuses confirmed prior to 20 weeks' gestation with the subsequent death of at least one twin. All the pregnancies were managed at The Royal Women's Hospital, Melbourne between 2006 and 2014. We excluded pregnancies of higher order multiples, the death of both twins simultaneously, and cases with incomplete outcome data. Maternal and neonatal data were reviewed. Of 46 pregnancies included, in 24 (52%), the dead twin was presenting. Gestational age at delivery was significantly earlier in these cases (mean difference: -5.0 weeks, 95% CI [-7.4, -2.6], p < .001), and emergency cesarean rates were higher 67% versus 32% (OR 4.29, 95% CI [1.25, 14.7], p = .02). There were no differences in the frequency of chorioamnionitis, preterm prelabor rupture of membranes, or placental abruption. Survival rates for co-twins were similar in both groups (presenting 83%; not presenting 91%; OR 0.41, 95% CI [0.07, 2.50], p = .29). The increase in neonatal morbidities was related to prematurity rather than to order. Findings were more common in dichorionic twins. Analysis was limited by a small sample size. If the dead twin is presenting, delivery is likely to occur earlier, with associated morbidity for the survivors. This is especially relevant for dichorionic twin pregnancies.

Multisite Experience of the Safety, Detection Rate and Diagnostic Performance of Fluciclovine (18F) Positron Emission Tomography/Computerized Tomography Imaging in the Staging of Biochemically Recurrent Prostate Cancer.

PURPOSE: Sensitive detection of cancer foci in men experiencing biochemical recurrence following initial treatment of prostate cancer is of great clinical significance with a possible impact on subsequent treatment choice. We describe a multisite experience of the efficacy and safety of the positron emission tomography/computerized tomography agent fluciclovine (18F) after biochemical recurrence. MATERIALS AND METHODS: A total of 596 patients underwent fluciclovine (18F) positron emission tomography/computerized tomography at 4 clinical sites. Detection rate determinations were stratified by the baseline prostate specific antigen value. Diagnostic performance was assessed against a histological reference standard in 143 scans. RESULTS: The subject level fluciclovine (18F) positron emission tomography/computer tomography detection rate was 67.7% (403 of 595 scans). Positive findings were detected in the prostate/bed and pelvic lymph node regions in 38.7% (232 of 599) and 32.6% of scans (194 of 596), respectively. Metastatic involvement outside the pelvis was detected in 26.2% of scans (155 of 591). The subject level detection rate in patients in the lowest quartile for baseline prostate specific antigen (0.79 ng/ml or less) was 41.4% (53 of 128). Of these patients 13 had involvement in the prostate/bed only, 16 had pelvic lymph node involvement without distant disease and 24 had distant metastases. The positive predictive value of fluciclovine (18F) positron emission tomography/computerized tomography scanning for all sampled lesions was 62.2%, and it was 92.3% and 71.8% for extraprostatic and prostate/bed involvement, respectively. Fluciclovine (18F) was well tolerated and the safety profile was not altered following repeat administration. CONCLUSIONS: Fluciclovine (18F) is well tolerated and able to detect local and distant prostate cancer recurrence across a wide range of prostate specific antigen values.

Treatment with anti-neonatal Fc receptor (FcRn) antibody ameliorates experimental epidermolysis bullosa acquisita in mice.

BACKGROUND AND PURPOSE: Pemphigus and pemphigoid diseases are characterized and caused predominantly by IgG autoantibodies targeting structural proteins of the skin. Their current treatment relies on general and prolonged immunosuppression that causes severe adverse events, including death. Hence, novel safe and more effective treatments are urgently needed. Due to its' physiological functions, the neonatal Fc receptor (FcRn) has emerged as a potential therapeutic target for pemphigus and pemphigoid, primarily because IgG is protected from proteolysis after uptake into endothelial cells. Thus, blockade of FcRn would reduce circulating autoantibody concentrations. However, long-term effects of pharmacological FcRn inhibition in therapeutic settings of autoimmune diseases are unknown. EXPERIMENTAL APPROACH: Therapeutic effects of FcRn blockade were investigated in a murine model of the prototypical autoantibody-mediated pemphigoid disease, epidermolysis bullosa acquisita (EBA). B6.SJL-H2s C3c/1CyJ mice with clinically active disease were randomized to receive either an anti-FcRn monoclonal antibody (4470) or an isotype control over 4 weeks. KEY RESULTS: While clinical disease continued to worsen in isotype control-treated mice, overall disease severity continuously decreased in mice injected with 4470, leading to almost complete remission in over 25% of treated mice. These clinical findings were paralleled by a reduction of autoantibody concentrations. Reduction of autoantibody concentrations, rather than modulating neutrophil activation, was responsible for the observed therapeutic effects. CONCLUSION AND IMPLICATIONS: The clinical efficacy of anti-FcRn treatment in this prototypical autoantibody-mediated disease encourages further development of anti-FcRn antibodies for clinical use in pemphigoid diseases and potentially in other autoantibody mediated diseases.

Reader Training for the Restaging of Biochemically Recurrent Prostate Cancer Using 18F-Fluciclovine PET/CT.

18F-Fluciclovine is a novel PET/CT tracer. This blinded image evaluation (BIE) sought to demonstrate that, after limited training, readers naïve to 18F-fluciclovine could interpret 18F-fluciclovine images from subjects with biochemically recurrent prostate cancer with acceptable diagnostic performance and reproducibility. The primary objectives were to establish individual readers' diagnostic performance and the overall interpretation (2/3 reader concordance) compared with standard-of-truth data (histopathology or clinical follow-up) and to evaluate interreader reproducibility. Secondary objectives included comparison to the expert reader and assessment of intrareader reproducibility. Methods:18F-Fluciclovine PET/CT images (n = 121) and corresponding standard-of-truth data were collected from 110 subjects at Emory University using a single-time-point static acquisition starting 5 min after injection of approximately 370 MBq of 18F-fluciclovine. Three readers were trained using standardized interpretation methodology and subsequently evaluated the images in a blinded manner. Analyses were conducted at the lesion, region (prostate, including bed and seminal vesicle, or extraprostatic, including all lymph nodes, bone, or soft-tissue metastasis), and subject level. Results: Lesion-level overall positive predictive value was 70.5%. The readers' positive predictive value and negative predictive value were broadly consistent with each other and with the onsite read. Sensitivity was highest for readers 1 and 2 (68.5% and 63.9%, respectively) whereas specificity was highest for reader 3 (83.6%). Overall, prostate-level sensitivity was high (91.4%), but specificity was moderate (48.7%). Interreader agreement was 94.7%, 74.4%, and 70.3% for the lesion, prostate, and extraprostatic levels, respectively, with associated Fleiss' κ-values of 0.54, 0.50, and 0.57. Intrareader agreement was 97.8%, 96.9%, and 99.1% at the lesion level; 100%, 100%, and 91.7% in the prostate region; and 83.3%, 75.0%, and 83.3% in the extraprostatic region for readers 1, 2, and 3, respectively. Concordance between the BIE and the onsite reader exceeded 75% for each reader at the lesion, region, and subject levels. Conclusion: Specific training in the use of standardized interpretation methodology for assessment of 18F-fluciclovine PET/CT images enables naïve readers to achieve acceptable diagnostic performance and reproducibility when staging recurrent prostate cancer.

Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations.

BACKGROUND: Influenza causes lower respiratory tract complications (LRTCs), particularly bronchitis and pneumonia, in both otherwise healthy adults and those with underlying conditions. The aim of this study was to assess the effect of oseltamivir treatment on the incidence of LRTCs leading to antibiotic treatment and hospitalizations following influenza illness. METHODS: We analyzed prospectively collected data on LRTCs and antibiotic use from 3564 subjects (age range, 13-97 years) with influenzalike illness enrolled in 10 placebo-controlled, double-blind trials of oseltamivir treatment. RESULTS: In adults and adolescents with a proven influenza illness, oseltamivir treatment reduced overall antibiotic use for any reason by 26.7% (14.0% vs 19.1% with placebo; P<.001) and the incidence of influenza-related LRTCs resulting in antibiotic therapy by 55% (4.6% vs 10.3% with placebo; P<.001). In those subjects considered at increased risk of complications, 74 (18.5%) of 401 placebo recipients developed an LRTC leading to antibiotic use compared with 45 (12.2%) of 368 oseltamivir recipients (34.0% reduction; P =.02). Hospitalization for any cause occurred in 18 (1.7%) of 1063 placebo recipients compared with 9 (0.7%) of 1350 oseltamivir-treated patients (59% reduction; P =.02). In contrast, among subjects with an influenzalike illness but without a confirmed influenza infection, the incidence of LRTCs (6.7% vs 5.3%), overall antibiotic use (19.7% vs 19.3%), or hospitalizations (1.7% vs 1.9%) was similar between placebo and oseltamivir recipients, respectively. CONCLUSION: Oseltamivir treatment of influenza illness reduces LRTCs, antibiotic use, and hospitalization in both healthy and "at-risk" adults.

The pharmacokinetics and tolerability of oseltamivir suspension in patients on haemodialysis and continuous ambulatory peritoneal dialysis.

BACKGROUND: Oseltamivir dose reduction is recommended for patients with end-stage renal disease (ESRD). However, dosing recommendations are not available for treatment or prophylaxis of influenza in these patients. This study assessed the pharmacokinetics and tolerability of oseltamivir in ESRD patients undergoing maintenance haemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD). METHODS: In this open-label, multiple-dose study, patients received 30 mg oral oseltamivir suspension over 6.5 weeks. This dose was predicted to be suitable for ESRD patients based on a 2-compartment model. HD patients received 9 doses given 1 h after the completion of alternate HD sessions (three times a week). CAPD patients received 6 doses given once weekly after a dialysate exchange. The primary parameters were peak plasma concentration (C(max)) and the area under the curve (AUC) for oseltamivir and oseltamivir carboxylate. RESULTS: In HD patients, the C(max) for oseltamivir carboxylate after single and repeated dosing were 943 and 1120 ng/ml, respectively. The mean AUC(0-42) was 31 600 ng h/ml for days 1-5 and 38 200 ng h/ml for days 38-43. Similarly, in CAPD patients, mean C(max) after the first and sixth doses were 885 and 849 ng/ml, respectively. The mean AUC(0-48) values for days 1-6 and days 36-43 were 33 400 and 32 400 ng h/ml, respectively. Oseltamivir was well-tolerated in both the patient groups. CONCLUSIONS: A 30 mg dose of oseltamivir given once weekly in CAPD or after alternate sessions in HD patients provides sufficient exposure to oseltamivir carboxylate to allow safe and effective anti-influenza treatment and prophylaxis.

Intravenous ibandronate injections in postmenopausal women with osteoporosis: one-year results from the dosing intravenous administration study.

OBJECTIVE: Although oral bisphosphonates are effective treatments for postmenopausal women with osteoporosis, oral dosing may be unsuitable for some patients. An efficacious intravenously administered bisphosphonate could be beneficial for such patients. Ibandronate, a potent nitrogen-containing bisphosphonate, can be administered using extended dosing intervals, either orally or by rapid intravenous injection. The aim of this study was to identify the optimal intravenous dosing regimen for ibandronate in postmenopausal women with osteoporosis. METHODS: In a randomized, double-blind, double-dummy, phase III, noninferiority study, we compared 2 regimens of intermittent intravenous injections of ibandronate (2 mg every 2 months and 3 mg every 3 months) with a regimen of 2.5 mg of oral ibandronate daily, the latter of which has proven antifracture efficacy. The study group comprised 1,395 women (ages 55-80 years) who were at least 5 years postmenopausal. All patients had osteoporosis (lumbar spine [L2-L4] bone mineral density [BMD] T score less than -2.5). Participants also received daily calcium (500 mg) and vitamin D (400 IU). The primary end point was change from baseline in lumbar spine BMD at 1 year. Changes in hip BMD and in the level of serum C-telopeptide of type I collagen (CTX) were also measured, as were safety and tolerability. RESULTS: At 1 year, mean lumbar spine BMD increases were as follows: 5.1% among 353 patients receiving 2 mg of ibandronate every 2 months, 4.8% among 365 patients receiving 3 mg of ibandronate every 3 months, and 3.8% among 377 patients receiving 2.5 mg of oral ibandronate daily. Both of the intravenous regimens not only were noninferior, but also were superior (P < 0.001) to the oral regimen. Hip BMD increases (at all sites) were also greater in the groups receiving medication intravenously than in the group receiving ibandronate orally. Robust decreases in the serum CTX level were observed in all arms of the study. Both of the intravenous regimens were well tolerated and did not compromise renal function. CONCLUSION: As assessed by BMD, intravenous injections of ibandronate (2 mg every 2 months or 3 mg every 3 months) are at least as effective as the regimen of 2.5 mg orally daily, which has proven antifracture efficacy, and are well tolerated.

Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic.

Recent cross species transmission of avian influenza has highlighted the threat of pandemic influenza. Oseltamivir (Tamiflu) has been shown to be effective in the treatment and prevention of epidemic influenza infection in adults, adolescents and children (> or = 1 year). Although oseltamivir has not been approved for prophylactic use in children, it has been shown to be effective. Oseltamivir is also active against avian influenza virus strains. Evidence suggests that lower doses or shorter durations of treatment/chemoprophylaxis other than those approved may not be effective and may contribute to emergence of viral resistance. Safety data from dose ranging studies show that 5 day courses of 150 mg twice daily for treatment and 6 week courses of 75 mg twice daily for prophylaxis were as well tolerated as the approved dose regimens. The use of oseltamivir in a pandemic is influenced by the goals of the pandemic plan developed by the responsible Government and Health Authority. To optimize use of antiviral medications, processes will be needed to collect, collate and report outcome data from treated patients and/or from use for chemoprophylaxis of pandemic influenza during the first-wave outbreaks. If oseltamivir is included in a national or regional pandemic plan, stockpiling of the material, either in the form of capsules or the bulk active pharmaceutical ingredient will be necessary. In the absence of a stockpile, there is no guarantee that an adequate supply of oseltamivir will be available.

Viral respiratory infection in schoolchildren: effects on middle ear pressure.

OBJECTIVE: To evaluate the effect of uncomplicated viral respiratory infections (colds) on middle ear pressure in healthy school-aged children. METHODS: Children (ages 2-12) with normal tympanograms before onset of illness had bilateral tympanometry daily except weekends for 2 weeks after the onset of a cold. Nasopharyngeal secretion obtained at onset of illness was cultured for bacterial pathogens of otitis media using selective agars and tested for rhinovirus, coronavirus, respiratory syncytial virus, influenza A and B, and parainfluenza 1-3 by reverse transcriptase polymerase chain reaction technology. Tympanometry was designated as abnormal with peak pressure of < or =-100 daPa or > or =50 daPa and/or a compliance peak of < 0.2 cm(3). RESULTS: Eighty-six colds were studied, 82 in schoolchildren (5-12 years old) and 4 in 2- to 3-year-olds. Abnormal negative middle ear pressure occurred at least once during the 2 weeks after onset in 57 (66%) of the 86 colds. Tympanometry was abnormal in the first week after onset in 50 (88%) of the 57 colds and was abnormal on a single day in 17 (30%) of the 57. The middle ear pressure abnormalities were intermittent and shifted from one ear to the other ear from day to day. Reverse transcriptase polymerase chain reaction was positive for a respiratory virus in 56 (65%) of the 86 illnesses. Rhinovirus was found in 48% and respiratory syncytial virus in 14%. Pathogenic bacteria (Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis) were detected in nasopharyngeal secretion in 29 (34%) of the 86 colds; the bacteria were in high titer (> or =10(3) cfu/mL) in 26 of the 29 positive specimens. None developed illness that required a visit to a physician. Age, detection of a respiratory virus, and presence of bacterial pathogen in the nasopharyngeal secretion had a negligible effect on the occurrence of abnormal tympanometry. Occurrence of negative middle ear pressure in winter-spring colds was significantly greater than in fall colds for unexplained reasons. CONCLUSIONS: Transient negative middle ear pressure occurred in two thirds of uncomplicated colds in healthy children. This negative pressure, which may facilitate secondary viral or bacterial otitis media, seems to result from viral infection of the nasopharynx and distal tube causing bilateral eustachian tube dysfunction. Tympanometry provides an objective measure of the potential beneficial effects of investigational treatments on the risk of eustachian tube dysfunction/otitis media.

Lack of pharmacokinetic interaction between the oral anti-influenza prodrug oseltamivir and aspirin.

Twelve volunteers completed a two-sequence, three-way crossover study of a single 900-mg aspirin dose and multiple doses of 75 mg of oseltamivir in the absence and presence of 900 mg of aspirin. The plasma and urine results demonstrated no pharmacokinetic interaction between oseltamivir and aspirin.

A population-dynamic model for evaluating the potential spread of drug-resistant influenza virus infections during community-based use of antivirals.

A mathematical model of influenza transmission dynamics is used to simulate the impact of neuraminidase inhibitor therapy on infection rates and transmission of drug-resistant viral strains. The model incorporates population age structure, seasonal transmission, immunity and inclusion of elderly nursing home residents or non-residents. Key parameter values are estimated from epidemiological, clinical and experimental data. The analysis examines the factors determining the population spread of antiviral resistance, and predicts no significant transmission of neuraminidase inhibitor resistant virus. This conclusion is robust even at high therapy levels and under conservative assumptions regarding the likely frequency of transmission of resistant virus. The predicted incidence of resistance following protracted usage reflects primary drug resistance, currently estimated as approximately 2% for neuraminidase inhibitor therapy. It is also shown that until high levels of therapy are attained, early treatment of symptomatic cases is more efficient (per unit of drug) at preventing infections than prophylactic therapy.

Pharmacokinetics of anti-influenza prodrug oseltamivir in children aged 1-5 years.

OBJECTIVE: The prodrug oseltamivir has been shown to be efficacious and safe for the treatment of influenza for patients 1 year of age or older; however, pharmacokinetic information was lacking for children below 5 years of age. This study was conducted to assess the metabolic and excretory capacity of oseltamivir and its active carboxylate metabolite in young children. METHODS: Twelve healthy children aged 1-5 years received a single oral suspension dose of oseltamivir (45 mg for 3-5 years, 30 mg for 1-2 years). Plasma and urine concentrations of oseltamivir and the carboxylate were determined by means of liquid chromatography/tandem mass spectrometry. RESULTS: Mean peak plasma concentration and area under the plasma concentration-time curve values normalized to milligram per kilogram oseltamivir dose in the 1- to 2-year group are lower than those in the 3- to 5-year group. Mean body weight normalized oral clearance of oseltamivir and its carboxylate in younger subjects aged 1-2 years (259 ml/min/kg and 12.2 ml/min/kg) were, respectively, 52% and 30% higher than those in older subjects aged 3-5 years (170 ml/min/kg and 9.4 ml/min/kg). CONCLUSION: The results demonstrate that infants as young as 1 year old can metabolize and excrete oseltamivir efficiently. The data derived from this study provide the starting dose of oseltamivir for further investigation in an efficacy study among influenza-infected infants less than 1 year of age.

Role of picornaviruses in flu-like illnesses of adults enrolled in an oseltamivir treatment study who had no evidence of influenza virus infection.

The primary objective of this study was to determine the role of picornavirus in flu-like episodes (temperature of > or =38.0 degrees C plus one respiratory and one constitutional symptom) among otherwise healthy adults enrolled in a placebo-controlled, double-blind, randomized oseltamivir treatment study. Combined nasal and pharyngeal swabs were collected at baseline for influenza cultures and picornavirus reverse transcription (RT)-PCR. In addition, acute- and convalescent-serum samples were obtained for serological studies of common respiratory pathogens. From a total of 719 subjects enrolled in the clinical trial within 36 h of the onset of symptoms, 475 (66%) had evidence of recent influenza A or B virus infections by means of culture and/or serological testing. Of the 244 remaining patients, 36 (15%) presented a seroconversion for at least one of the common respiratory viruses or atypical pathogens. An RT-PCR assay for the picornavirus 5" noncoding region (NCR) was positive in a subset of 15 (19%) of 78 patients with flu-like illnesses of undetermined etiology. Sequence analysis of the picornavirus 5" NCR amplicons revealed that 14 (93%) of them had greater homology to rhinoviruses, whereas 1 (7%) was related to enteroviruses. Interestingly, median total symptom scores and oral temperatures of picornavirus-positive patients (n = 15) and placebo-treated influenza virus-positive patients (n = 161) were similar over a 3-week period. We conclude that, among the influenza virus-negative preselected cases of this study, rhinoviruses were relatively frequent pathogens associated with important respiratory and systemic symptoms.

Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis.

We determined the efficacy of postexposure prophylaxis (PEP) and treatment of ill index cases with oseltamivir, in an attempt to prevent influenza transmission in households, in a study conducted in 277 households with 298 index cases (62% with laboratory-confirmed influenza) and 812 contacts aged > or =1 year. Contacts were randomized by household to receive treatment (5 days; n=402), if illness developed, or PEP for 10 days (n=410), and the number of households with at least 1 contact developing laboratory-confirmed influenza was measured. PEP provided a protective efficacy of 58.5% (95% confidence interval [CI], 15.6%-79.6%; P=.0114) for households against proven influenza and 68.0% (95% CI, 34.9%-84.2%; P=.0017) for individual contacts, compared with treatment of index cases alone. No oseltamivir-resistant variants were detected in treated index cases or contacts. PEP of household contacts of those with influenza reduces the secondary spread of influenza in families when the initial household case is treated.