Association of haemoglobin levels in the first trimester and at 26-30 weeks with fetal and neonatal outcomes: a secondary analysis of the Global Network for Women's and Children's Health's ASPIRIN Trial.

OBJECTIVE: Limited data are available from low- and middle-income countries (LMICs) on the relationship of haemoglobin levels to adverse outcomes at different times during pregnancy. We evaluated the association of haemoglobin levels in nulliparous women at two times in pregnancy with pregnancy outcomes. DESIGN: ASPIRIN Trial data were used to study the association between haemoglobin levels measured at 6+0 -13+6  weeks and 26+0 -30+0  weeks of gestation with fetal and neonatal outcomes. SETTING: Obstetric care facilities in Pakistan, India, Kenya, Zambia, The Democratic Republic of the Congo and Guatemala. POPULATION: A total of 11 976 pregnant women. METHODS: Generalised linear models were used to obtain adjusted relative risks and 95% CI for adverse outcomes. MAIN OUTCOME MEASURES: Preterm birth, stillbirth, neonatal death, small for gestational age (SGA) and birthweight <2500 g. RESULTS: The mean haemoglobin levels at 6+0 -13+6  weeks and at 26-30 weeks of gestation were 116 g/l (SD 17) and 107 g/l (SD 15), respectively. In general, pregnancy outcomes were better with increasing haemoglobin. At 6+0 -13+6  weeks of gestation, stillbirth, SGA and birthweight <2500 g, were significantly associated with haemoglobin of 70-89 g/l compared with haemoglobin of 110-129 g/l The relationships of adverse pregnancy outcomes with various haemoglobin levels were more marked at 26-30 weeks of gestation. CONCLUSIONS: Both lower and some higher haemoglobin concentrations are associated with adverse fetal and neonatal outcomes at 6+0 -13+6  weeks and at 26-30 weeks of gestation, although the relationship with low haemoglobin levels appears more consistent and generally stronger. TWEETABLE ABSTRACT: Both lower and some higher haemoglobin concentrations were associated with adverse fetal and neonatal outcomes at 6-13 weeks and 26-30 weeks of gestation.

A prediction model of military combat and training exposures on VA service-connected disability: a CENC study.

Background: Research has shown that number of and blast-related Traumatic Brain Injuries (TBI) are associated with higher levels of service-connected disability (SCD) among US veterans. This study builds and tests a prediction model of SCD based on combat and training exposures experienced during active military service.Methods: Based on 492 US service member and veteran data collected at four Department of Veterans Affairs (VA) sites, traditional and Machine Learning algorithms were used to identify a best set of predictors and model type for predicting %SCD ≥50, the cut-point that allows for veteran access to 0% co-pay for VA health-care services.Results: The final model of predicting %SCD ≥50 in veterans revealed that the best blast/injury exposure-related predictors while deployed or non-deployed were: 1) number of controlled detonations experienced, 2) total number of blast exposures (including controlled and uncontrolled), and 3) the total number of uncontrolled blast and impact exposures.Conclusions and Relevance: We found that the highest blast/injury exposure predictor of %SCD ≥50 was number of controlled detonations, followed by total blasts, controlled or uncontrolled, and occurring in deployment or non-deployment settings. Further research confirming repetitive controlled blast exposure as a mechanism of chronic brain insult should be considered.

Pain and chronic mild traumatic brain injury in the US military population: a Chronic Effects of Neurotrauma Consortium study.

PRIMARY OBJECTIVES: To describe the association between mild traumatic brain injury (mTBI) and pain intensity and pain interference outcomes while accounting for potential confounders and mediators including environmental factors and comorbidities in a cohort of US Veterans of the Iraq and Afghanistan wars. RESEARCH DESIGN: Cross-sectional snapshot of baseline data from a prospective, longitudinal study. METHODS: Effects of mTBI on pain intensity and pain interference were compared between participants with or without mTBI exposure. Data were analysed using covariate-adjusted regression analyses as well as structural equation modelling (SEM) methods to assess the robustness of findings across different modelling assumptions. As results of the two approaches were consistent with respect to the overall association between mTBI exposure and pain, the results focus primarily on the SEM findings. RESULTS: The mTBI exposed group reported significantly greater indices of post-traumatic stress disorder (PTSD), depression, anxiety and sleep disturbance. After accounting for other factors, mTBI exposure was significantly, but indirectly associated with the pain interference and pain intensity outcomes. CONCLUSIONS: mTBI is strongly associated with pain intensity and pain interference in this sample. However, the effect appears to be mediated by other common mTBI comorbidities: PTSD, depression, anxiety and sleep disturbance.

The Chronic Effects of Neurotrauma Consortium (CENC) multi-centre observational study: Description of study and characteristics of early participants.

PRIMARY OBJECTIVES: To establish and comprehensively evaluate a large cohort of US veterans who served in recent military conflicts in order to better understand possible chronic and late-life effects of mild traumatic brain injury (mTBI), including those that may stem from neurodegeneration. RESEARCH DESIGN: Cross-sectional and prospective longitudinal. METHODS AND PROCEDURES: Inclusion criteria are prior combat exposure and deployment(s) in Operation Enduring Freedom, Operation Iraqi Freedom or one of their follow-on conflicts (collectively OEF/OIF). Effects of mTBI will be assessed by enrolling participants across the entire spectrum of mTBI, from entirely negative to many mTBIs. Longitudinal assessments consist of in-person comprehensive testing at least every 5 years, with interval annual telephonic testing. The primary outcome is the composite score on the NIH Toolbox neuropsychological test battery. Assessments also include structured interviews, questionnaires, traditional neuropsychological testing, motor, sensory and vestibular functions, neuroimaging, electrophysiology, genotypes and biomarkers. MAIN OUTCOMES AND RESULTS: The authors fully describe the study methods and measures and report demographic and exposure characteristics from the early portion of the cohort of OEF/OIF veterans. CONCLUSIONS: This centrepiece observational study of the Chronic Effects of Neurotrauma Consortium (CENC) is successfully launched and, within several years, should provide fertile data to begin investigating its aims.

Effects of trial repetition, limb side, intraday and inter-week variation on vertical and craniocaudal ground reaction forces in clinically normal Labrador Retrievers.

OBJECTIVES: To document the contributions of trial repetition, limb side, and intraday and inter-week measurements on variation in vertical and craniocaudal ground reaction force data. METHODS: Following habituation, force and time data were collected for all four limbs of seven Labrador Retrievers during sets of five valid trot trials. Each set was performed twice daily (morning and afternoon), every seven days for three consecutive weeks. A repeated measures analysis of variance was used to determine the effects of limb, trial, intraday, and inter-week factors on ground reaction force data for the thoracic and pelvic limbs. RESULTS: Of the four factors evaluated, variation due to trial repetition had the largest magnitude of effect on ground reaction forces. Trial within a set of data had an effect on all craniocaudal, but not vertical, ground reaction force variables studied, for the thoracic limbs. The first of five trials was often different from later trials. Some thoracic limb and pelvic limb variables were different between weeks. A limb side difference was only apparent for pelvic limb vertical ground reaction force data. Only pelvic limb craniocaudal braking variables were different between sets within a day. DISCUSSION AND CLINICAL SIGNIFICANCE: When controlling for speed, handler, gait, weight and dog breed, variation in ground reaction forces mainly arise from trial repetition and inter-week data collection. When using vertical peak force and impulse to evaluate treatment, trial repetition and inter-week data collection should have minimal effect of the data.

Monitoring and impact of fluconazole serum and cerebrospinal fluid concentration in HIV-associated cryptococcal meningitis-infected patients.

OBJECTIVES: The aim of the present study was to assess fluconazole pharmacokinetic measures in serum and cerebrospinal fluid (CSF); and the correlation of these measures with clinical outcomes of invasive fungal infections. METHODS: A randomized trial was conducted in HIV-infected patients receiving three different regimens of fluconazole plus amphotericin B (AmB) for the treatment of cryptococcal meningitis. Regimens included fluconazole 400 mg/day+AmB (AmB+Fluc400) or fluconazole 800 mg/day+AmB (AmB+Fluc800) (14 days followed by fluconazole alone at the randomized dose for 56 days); or AmB alone for 14 days followed by fluconazole 400 mg/day for 56 days. Serum (at 24 h after dosing) and CSF samples were taken at baseline and days 14 and 70 (serum only) for fluconazole measurement, using gas-liquid chromatography. RESULTS: Sixty-four treated patients had fluconazole measurements: 11 in the AmB group, 12 in the AmB+Fluc400 group and 41 in the AmB+Fluc800 group. Day 14 serum concentration geometric means were 24.7 mg/L for AmB+Fluc400 and 37.0 mg/L for AmB+Fluc800. Correspondingly, CSF concentration geometric means were 25.1 mg/L and 32.7 mg/L. Day 14 Serum and CSF concentrations were highly correlated with AmB+Fluc800 (P<0.001, r=0.873) and AmB+Fluc400 (P=0.005, r=0.943). Increased serum area under the curve (AUC) appears to be associated with decreased mortality at day 70 (P=0.061, odds ratio=2.19) as well as with increased study composite endpoint success at days 42 and 70 (P=0.081, odds ratio=2.25 and 0.058, 2.89, respectively). CONCLUSION: High fluconazole dosage (800 mg/day) for the treatment of HIV-associated cryptococcal meningitis was associated with high serum and CSF fluconazole concentration. Overall, high serum and CSF concentration appear to be associated with increased survival and primary composite endpoint success.

Initiation of behavior by single neurons: the role of behavioral context.

Flying crickets avoid sources of ultrasound, possibly echolocating bats, by making rapid steering movements that turn them away from the stimulus. Electrical stimulation of a single, identified sensory interneuron (Int-1) elicits avoidance steering; depressing its response to ultrasound abolishes avoidance steering. Int-1 is necessary and sufficient for this behavior but only while the cricket is in flight. Thus, the sufficiency of Int-1 for eliciting this behavior is contingent on behavioral context.

Behavioral dissociation of dishabituation, sensitization, and inhibition in Aplysia.

Three forms of nonassociative learning (habituation, dishabituation, and sensitization) have commonly been explained by a dual-process view in which a single decrementing process produces habituation and a single facilitatory process produces both dishabituation and sensitization. A key prediction of this view is that dishabituation and sensitization should always occur together. However, we show that dishabituation and sensitization, as well as an additional process, inhibition, can be behaviorally dissociated in Aplysia by (i) their differential time of onset, (ii) their differential sensitivity to stimulus intensity, and (iii) their differential emergence during development. A simple dual-process view cannot explain these results; rather, a multiprocess view appears necessary to account for nonassociative learning in Aplysia.

18 F-sodium fluoride positron emission tomography of the racing Thoroughbred fetlock: Validation and comparison with other imaging modalities in nine horses.

BACKGROUND: Early and accurate detection of stress remodelling in racehorses is of utmost importance to prevent catastrophic injuries. Current imaging techniques have limitations in assessing early changes predisposing to catastrophic breakdowns. Positron emission tomography (PET) using 18 F-sodium fluoride (18 F-NaF) is a sensitive method for the detection of early bone turnover and may improve early recognition of subtle injuries. OBJECTIVES: To validate the clinical use of 18 F-NaF PET in Thoroughbred racehorses, to assess the value of PET in the detection of bone lesions and to compare PET results with findings of other advanced imaging modalities, clinical examination and pathology. STUDY DESIGN: Experimental exploratory study. METHODS: Twenty fetlocks from nine Thoroughbred racehorses were imaged using 18 F-NaF PET, computed tomography (CT) and scintigraphy. Five fetlocks were also imaged with magnetic resonance imaging and four fetlocks were also examined histologically. Imaging findings were independently reviewed by three board certified radiologists. Imaging, clinical and histopathological findings were correlated. RESULTS: PET imaging was well-tolerated by all horses. PET detected focal areas of 18 F-NaF uptake in instances where other imaging modalities did not identify abnormalities, in particular in the proximal sesamoid bones. Maximal standardised uptake values could be measured to quantify the activity of lesions. Areas of 18 F-NaF uptake corresponded to regions of increased vascularity and increased osteoblastic activity. MAIN LIMITATIONS: Limited number of cases. CONCLUSIONS: 18 F-NaF PET imaging of the Thoroughbred fetlock is feasible and compares favourably with other imaging modalities in detecting stress remodelling in Thoroughbred racehorses. PET appears to be a beneficial imaging modality when used for early detection of stress remodelling in an effort to prevent catastrophic musculoskeletal injuries in this population of horses.

Short-course ciprofloxacin treatment of acute uncomplicated urinary tract infection in women. The minimum effective dose. The Urinary Tract Infection Study Group [corrected].

BACKGROUND: Three studies were undertaken to determine the minimum effective dosing regimen of ciprofloxacin for the treatment of acute, symptomatic, uncomplicated lower urinary tract infection. METHODS: All studies were multicenter, prospective, randomized, double-blind trials. A total of 970 evaluable patients with a diagnosis of urinary tract infection received oral ciprofloxacin (200 mg to 500 mg daily in one or two divided doses for 1, 3, 5, or 7 days) or norfloxacin (400 mg twice daily [BID] for 7 days). The primary measure of efficacy was bacteriologic eradication at the end of therapy. RESULTS: In study 1, bacteriologic eradication was reported in 95 (89%) and 101 (98%) of patients in the groups who received ciprofloxacin, 500-mg single dose and 250 mg BID for 7 days, respectively. Clinical success occurred in 101 patients (94%) who received a 500-mg single dose and in 103 patients (100%) who were administered 250 mg BID for 7 days. In study 2, eradication rates in the groups who received ciprofloxacin, 100 mg BID for 3 days, 250 mg BID for 3 days, and 250 mg BID for 7 days, were 98 (93%), 95 (90%), and 98 (93%), respectively. Clinical success was reported in 102 (97%), 105 (100%), and 104 (98%) of the patients, respectively. In study 3, the eradication rates in the groups who received ciprofloxacin in dosages of 500 mg once daily for 3 days and 500 mg once daily for 5 days and norfloxacin in a dosage of 400 mg BID for 7 days were 137 (92%), 134 (90%), and 133 (94%) of the women, respectively. Clinical success was the same (97%) in all three groups. Overall, short-course (either 3- or 5-day) therapy with ciprofloxacin was statistically equivalent to conventional (7-day) therapy with either ciprofloxacin or norfloxacin. Single-dose ciprofloxacin therapy was statistically less effective than conventional treatment. CONCLUSIONS: Ciprofloxacin at a dosage of 100 mg BID for 3 days was the minimum effective dose for the treatment of uncomplicated urinary tract infection in women.

Once-daily fosinopril in the treatment of hypertension.

This multicenter, dose-ranging study evaluated the antihypertensive effectiveness of once-daily administration of fosinopril sodium in 220 patients with supine diastolic blood pressure of 95-115 mm Hg. After a 4-week placebo period, patients were randomly assigned to double-blind therapy with either placebo or 10, 40, or 80 mg fosinopril once daily for 4 weeks. If treatment goals were not met, chlorthalidone 25 mg/day was added for weeks 5 to 8. Thereafter, patients could enter the long-term, open-label phase and receive 10-80 mg/day fosinopril plus chlorthalidone, if needed. After 4 weeks of monotherapy, the average decreases in supine diastolic blood pressure were 9% (10 mg), 11.5% (40 mg), and 12.5% (80 mg) compared with 6% in the placebo group. After 8 weeks, the average decreases, with or without diuretic therapy, were 12.5-18.2%, compared with 10.8% with placebo. Blood pressure continued to be well controlled, and the patients showed no evidence of tachyphylaxis or tolerance through 12-15 months of treatment. Fosinopril was well tolerated. During the short-term phase, no patient withdrew because of adverse events possibly related to fosinopril; during the long-term phase, nine of 148 patients (6.1%) withdrew for that reason. In patients with mild-to-moderate hypertension, once-daily fosinopril (40 and 80 mg) provided significant antihypertensive effects with or without diuretic therapy. The 10 mg dose was effective in some patients and may be considered a starting dose.

Sedative effects of antihistamines: safety, performance, learning, and quality of life.

Antihistamines are frequently part of the treatment regimen for seasonal and perennial allergic rhinitis occurring alone or in conjunction with associated airway disorders, such as asthma, sinusitis, and otitis media with effusion. These agents are also frequently prescribed for the treatment of urticaria to eliminate the need for long-term corticosteroids. This paper reviews the side-effect profile of the sedating and nonsedating agents (a classification given these drugs by the US Food and Drug Administration) in terms of patient satisfaction and quality-of-life parameters. Because the sedating antihistamines cross the blood-brain barrier more quickly and easily than the nonsedating antihistamines, they produce more central nervous system (CNS) effects, further exacerbating the decreases in decision-making, verbal learning, and psychomotor skills already experienced by the patient with allergic rhinitis. In contrast the now-preferred nonsedating agents do not readily cross the blood-brain barrier, do not produce CNS side effects, and, therefore, do not cause sedation or performance impairment. The nonsedating agents provide a safer alternative for patients with allergic rhinitis. Their use can increase patient satisfaction with the health care received.

A multicenter trial comparing the efficacy and safety of cefuroxime axetil and cefaclor in pneumonia of adults.

The 185 hospitalized patients (aged 19 to 95 years) with pneumonia were randomly assigned to receive 500 mg of cefuroxime axetil orally (250 mg q12h), 1,000 mg of cefuroxime axetil orally (500 mg q12h), or 1,500 mg of cefaclor orally (500 mg q8h), daily, for a mean of nine days. Among the 151 evaluable patients, clinical cure was noted in 58% of the 500-mg cefuroxime axetil group, 94% of the 1,000-mg cefuroxime axetil group, and 88% of the cefaclor group, and clinical improvement in 32%, 4%, and 9%. Bacteriologic outcome was similar in the three groups. Adverse events were minor and comparable among the treatment groups. Cefuroxime axetil is a safe and effective oral antimicrobial for the treatment of pneumonia in adults.

HIV-1 gp41 envelope IgA is frequently elicited after transmission but has an initial short response half-life.

Prevention of HIV-1 transmission at mucosal surfaces will likely require durable pre-existing mucosal anti-HIV-1 antibodies (Abs). Defining the ontogeny, specificities and potentially protective nature of the initial mucosal virus-specific B-cell response will be critical for understanding how to induce protective Ab responses by vaccination. Genital fluids from patients within the earliest stages of acute HIV-1 infection (Fiebig I-VI) were examined for multiple anti-HIV specificities. Gp41 (but not gp120) Env immunoglobulin (Ig)A Abs were frequently elicited in both plasma and mucosal fluids within the first weeks of transmission. However, shortly after induction, these initial mucosal gp41 Env IgA Abs rapidly declined with a t(½) of ∼2.7 days. B-cell-activating factor belonging to the TNF family (BAFF) was elevated immediately preceding the appearance of gp41 Abs, likely contributing to an initial T-independent Ab response. HIV-1 transmission frequently elicits mucosal HIV-1 envelope-specific IgA responses targeted to gp41 that have a short half-life.

In vitro biomechanical comparison of load to failure testing of a canine unconstrained medial compartment elbow arthroplasty system and normal canine thoracic limbs.

Elbow dysplasia, primarily affecting the medial compartment, is the most common cause of lameness in the thoracic limb. Elbow arthroplasty is an option for end stage or severely affected patients. The purpose of this study was to compare ex vivo axial load to failure of an implanted novel elbow arthroplasty system to control limbs. The partial arthroplasty is a medial compartmental, unconstrained system, intended to allow conversion to total arthroplasty. We hypothesized that there would not be any significant difference between implanted and controlled limbs when loaded to failure. Six pairs of medium mixed breed canine cadaveric thoracic limbs were prepared for comparison of failure loading of control and implanted limbs. Axial compression was performed using a mechanical testing system. Failure loads were normalized to bodyweight. The mean normalized failure load (N/kg) for the implanted limbs and control limbs were 2.47 (range: 1.62-3.38) and 2.68 (range: 2.25-3.25), respectively. An implanted to control ratio of 0.93 ± 0.19 was calculated. The difference between paired control and implanted limbs in normalized failure loading was not significant (p = 0.38). There were not any differences noted in the yield load (p = 0.30), stiffness (p = 0.62), or energy (0.58). Failure modes were recorded. We concluded that the differences between implanted and control limbs in supra-physiologic axial load to failure were not significant.

Predictors of poor clinical outcome of cryptococcal meningitis in HIV-infected patients.

The aim of this study was to identify baseline prognostic factors for poor clinical outcome of HIV-associated cryptococcal meningitis. We conducted a trial in Thailand and the USA comparing low- and high-dose concomitant use of amphotericin B and fluconazole for HIV-associated cryptococcal meningitis to amphotericin B followed by fluconazole. Subjects who were either alive and cerebrospinal fluid (CSF) culture-positive or dead were considered to have a poor outcome. At day 14, baseline characteristics associated with poor outcome included: low weight, high CSF cryptococcal antigen (CrAg) titre and low CSF white blood cell (WBC) count. At day 70, the associated baseline characteristics included: CSF CrAg titre >1:1024 and low Karnofsky performance status. Overall, consistent with published findings, low weight, high CSF CrAg titre and low CSF WBC counts at baseline were predictors for poor clinical outcome. In addition, we found that low Karnofsky performance status was predictive of poor outcome. Prompt management with appropriate antifungal therapy for this particular group of patients may improve the outcomes.

International collaboration between US and Thailand on a clinical trial of treatment for HIV-associated cryptococcal meningitis.

BACKGROUND: International clinical trials can provide scientific and logistic benefits in spite of the many challenges. Determining whether a country, especially a developing country, is an appropriate location for the research should include in-country consultation and partnering to assess its social value for the population; that treatments are relevant for the population under study; and that the research infrastructure and ethical oversight are adequate. Collaboration increases the likelihood of study success and helps ensure that benefits accrue to recruited populations and their community. PURPOSE: This paper describes our experiences on a bi-national study and may provide guidance for those planning to engage in future collaborations. METHODS: A Thai and United States team collaborated to develop and implement a phase II clinical trial for HIV-associated cryptococcal meningitis to assess safety and tolerability of combination therapy vs. standard treatment. Clinical and cultural differences, regulatory hurdles and operational issues were addressed before and during the study to ensure a successful collaboration between the 2 groups. RESULTS: The international multicenter study allowed for more rapid enrollment, reduced costs to complete the study, sharing of the benefits of research, greater generalizability of results and capacity building in Thailand; quality metrics in Thailand were equivalent to or better than those in the U.S. CONCLUSIONS: Conducting successful clinical trials internationally requires early and ongoing collaboration to ensure the study meets sites' requirements and expectations, conforms to varying national regulations, adheres to data quality standards and is responsive to the health needs of studied populations.

Comparative studies of cefprozil in the management of skin and soft-tissue infections.

Six multicenter clinical trials comparing cefprozil with cefaclor, amoxicillin-clavulanate or erythromycin in the management of skin and soft-tissue infections caused by susceptible bacteria demonstrate that cefprozil, given once or twice daily, is an effective chemotherapeutic agent in this context. Its pharmacokinetic behavior is compatible with once-daily or twice-daily administration, with a probability of improved patient compliance. Safety and tolerability compare favorably with other agents used in skin and soft-tissue infections.

Clinical trials of cefprozil for treatment of skin and skin-structure infections: review.

Limitations of currently used antimicrobial agents for the treatment of skin and skin-structure infections (e.g., increased resistance to penicillin and erythromycin and inconvenient dosing schedules) have led to an adjustment in the kinds of antimicrobial agents prescribed for these diseases. Three recently completed clinical studies have demonstrated some therapeutic advantages of cefprozil, a new broad-spectrum oral cephalosporin, over cefaclor and erythromycin in the treatment of skin and skin-structure infections. Specifically, cefprozil offers clinical efficacy equivalent to those of cefaclor and erythromycin both at lower total doses and on a less frequent dosing schedule (once or twice daily vs. three to four times daily). The advantage of once-daily or twice-daily dosing with cefprozil may contribute to patient convenience and compliance.