Predictive index for adverse perinatal outcome in pregnancies complicated by fetal growth restriction.

OBJECTIVES: To develop and validate an index predictive of adverse perinatal outcome (APO) in pregnancies meeting the consensus-based criteria for fetal growth restriction (FGR) endorsed by the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG). METHODS: This was a retrospective analysis of consecutive singleton non-anomalous gestations meeting the ISUOG-endorsed criteria for FGR at a single tertiary care center from November 2010 to August 2020. The dataset was divided randomly into a development set (two-thirds) and a validation set (one-third). The primary composite APO comprised one or more of: perinatal demise, Grade III-IV intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), seizures, hypoxic ischemic encephalopathy (HIE), necrotizing enterocolitis (NEC), sepsis, bronchopulmonary dysplasia (BPD) and length of stay in the neonatal intensive care unit (NICU) > 7 days. Regression analysis incorporated clinical factors readily available at the time of FGR diagnosis. The sum of ß coefficient-based weights yielded an index score, the performance of which was assessed in the validation set. Score cut-offs were selected to identify 'high-risk' and 'low-risk' ranges for which positive (PPV) and negative (NPV) predictive values and positive (LR+) and negative (LR-) likelihood ratios were calculated. RESULTS: Of the 875 consecutive pregnancies that met the criteria for FGR and were included in the study cohort, 405 (46%) were complicated by one or more components of the composite APO, including 54 (6%) perinatal deaths, 22 (3%) neonates with Grade III-IV IVH and/or PVL, nine (1%) with seizures and/or HIE, 91 (10%) with BPD, 57 (7%) with sepsis, 21 (2%) with NEC, and 361 (41%) who remained in the NICU > 7 days. In addition, 270 (31%) pregnancies were delivered by Cesarean section for non-reassuring fetal status, 43 (5%) were admitted to the NICU for < 7 days, 79 (9%) had 5-min Apgar score < 7, 125/631 (20%) had a cord gas pH ≤ 7.1 and 35/631 (6%) had a base excess ≥ 12 mmol/L. The predictive index we developed included seven factors available at the time of FGR diagnosis: hypertensive disorder of pregnancy (HDP) (+8 points), chronic hypertension without HDP (+4 points), gestational age ≤ 32 weeks (+5 points), absent or reversed end-diastolic flow in the umbilical artery (+8 points), prepregnancy body mass index ≥ 35 kg/m2 (+3 points), isolated abdominal circumference < 3rd percentile (-4 points) and non-Hispanic black race (-2 points). The bias-corrected bootstrapped (1000 replicates) area under the receiver-operating-characteristics curve (AUC) of the predictive index for composite APO in the validation group was 0.88 (95% CI, 0.84-0.92), which was similar to that in the development group (AUC, 0.86 (95% CI, 0.82-0.89); P = 0.34). In the total cohort, 40% of pregnancies had a low-risk index score (≤ 2), associated with a NPV of 85% (95% CI, 81-88%) and a LR- of 0.21 (95% CI, 0.16-0.27), and 23% had a high-risk index score (≥ 10), associated with a PPV of 96% (95% CI, 93-98%) and a LR+ of 27.36 (95% CI, 14.33-52.23). Of the remaining pregnancies that had an intermediate-risk score, 50% were complicated by composite APO. CONCLUSION: An easy-to-use index incorporating seven clinical factors readily available at the time of FGR diagnosis is predictive of APO and may prove useful in counseling and management of pregnancies meeting the ISUOG-endorsed criteria for FGR. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Shaken baby syndrome: assessment, intervention, & prevention.

Child abuse and neglect continue to be parts of a disturbing reality in both the United States and the world. Despite significant advances in the identification and treatment of child abuse, health care professionals are still attempting to grasp the extent of the physiological and psychological effects of child maltreatment and injury. Child abuse, in all of its forms, is preventable, and more must be done to decrease its incidence. Shaken baby syndrome is one of the most deadly and devastating forms of child abuse and is characterized by a traumatic brain injury caused by the violent shaking of an infant. Recognition of high-risk families, combined with education of parents and other caregivers are key to prevention of shaken baby syndrome.

Phase I/IIa safety, immunogenicity, and efficacy trial of NYVAC-Pf7, a pox-vectored, multiantigen, multistage vaccine candidate for Plasmodium falciparum malaria.

Candidate malaria vaccines have failed to elicit consistently protective immune responses against challenge with Plasmodium falciparum. NYVAC-Pf7, a highly attenuated vaccinia virus with 7 P. falciparum genes inserted into its genome, was tested in a phase I/IIa safety, immunogenicity, and efficacy vaccine trial in human volunteers. Malaria genes inserted into the NYVAC genome encoded proteins from all stages of the parasite's life cycle. Volunteers received three immunizations of two different dosages of NYVAC-Pf7. The vaccine was safe and well tolerated but variably immunogenic. While antibody responses were generally poor, cellular immune responses were detected in >90% of the volunteers. Of the 35 volunteers challenged with the bite of 5 P. falciparum-infected Anopheles mosquitoes, 1 was completely protected, and there was a significant delay in time to parasite patency in the groups of volunteers who received either the low or high dose of vaccine compared with control volunteers.

Phase I safety and immunogenicity testing of clinical lots of the synthetic Plasmodium falciparum vaccine SPf66 produced under good manufacturing procedure conditions in the United States.

Two clinical lots of alum-adsorbed SPf66 vaccine produced in the United States were evaluated in separate, open-label, Phase I clinical trials involving 15 healthy, malaria-naive, 18-45-year old men and women. Subjects received 2 mg doses subcutaneously in alternate arms at 0, one, and six months. Safety was assessed by monitoring local and systemic reactions and laboratory parameters. The most common side effects were erythema and local tenderness at the site of injection, which increased in frequency with subsequent doses of vaccine. These local reactions were considered mild and resolved within 24-48 hr. Eleven of 14 volunteers who received all three doses of vaccine seroconverted by enzyme-linked immunosorbent assay. The distribution of high, medium, and low nonresponders was comparable with that seen in trials of Colombian-produced vaccine. One high responder developed antibodies reactive with asexual stage parasite antigens by immunofluorescence and immunoblot. The results indicated that at full adult doses, SPf66 of U.S. origin is mildly reactogenic and induces immune responses similar to those reported for SPf66 of Colombian origin.

Inhibition of dihydropyridine-sensitive calcium entry in hypoxic relaxation of airway smooth muscle.

Hypoxia dilates airways in vivo and reduces active tension of airway smooth muscle in vitro. To determine whether hypoxia impairs Ca2+ entry through voltage-dependent channels (VDC), we tested the ability of dihydropyridines to modulate hypoxia-induced relaxation of KCl- and carbamyl choline (carbachol)-contracted porcine bronchi. Carbachol- or KCl-contracted bronchial rings were exposed to progressive hypoxia in the presence or absence of 1 microM BAY K 8644 (an L-type-channel agonist). In separate experiments, rings were contracted with carbachol or KCl, treated with nifedipine (a VDC antagonist), and finally exposed to hypoxia. BAY K 8644 prevented hypoxia-induced relaxation in KCl-contracted bronchi. Nifedipine (10(-5) M) totally relaxed KCl- contracted bronchi. Carbachol-contracted bronchi were only partially relaxed by nifedipine but were completely relaxed when the O2 concentration of the gas was reduced from 95 to 0%. These data indicate that hypoxia can reduce airway smooth muscle tone by limiting entry of Ca2+ through a dihydropyridine-sensitive pathway, but that other mechanisms also contribute to hypoxia-induced relaxation of carbachol-contracted bronchi.

Evaluation of temporary atrial pacing leads.

Thirty-five patients were randomized to receive either the Medtronic 6500 or one of two braided multifilament temporary pacing leads in the atrium following open heart surgery. Sensing performance was judged by amplitude, slew rate, and the proportion of patients with an adequate sensing threshold. Pacing performance was assessed with measures of impedance, threshold voltage, current, and energy. The Medtronic 6500 demonstrated superior sensing and lower energy consumption compared to braided multifilament leads. This type of lead may offer advantages when using atrial synchronous temporary pacing systems.

The effects of neonatal capsaicin administration on trigeminal nerve chemoreceptors in the rat nasal cavity.

Trigeminal nerve fibers in the nasal cavity respond to a variety of volatile chemical stimuli. Some of these trigeminal nerve fibers have been suggested to be capsaicin-sensitive and thus belong to a class of pain receptor rather than constituting a separate class of chemoreceptor. Our current results confirm this suggestion. Trigeminal nerve responses to volatile chemical stimuli were eliminated in rats which were injected with capsaicin on the second day of life. Animals whose nerves were unresponsive to chemical stimuli also exhibited a loss of intraepithelial peptide-immunoreactive fibers in their nasal cavities. The results of this study suggest that trigeminal nerve fibers in the nasal cavity which respond to chemical stimuli may be polymodal nociceptors which contain substance P, calcitonin gene-related peptide, or perhaps other neuropeptides.

Corelease of neuropeptide Y like immunoreactivity with catecholamines from the adrenal gland during splanchnic nerve stimulation in anesthetized dogs.

The release of neuropeptide Y like immunoreactivity (NPY-li) from the adrenal gland was studied in relation to the secretion of catecholamines (CA: NE, norepinephrine; E, epinephrine) during the left splanchnic nerve stimulation in thiopental-chloralose anesthetized dogs (n = 16). Plasma concentrations of NE, E, and NPY-li were determined in the left adrenal venous and aortic blood. Adrenal outputs of NPY-li, NE, and E were 2.4 +/- 0.4, 1.4 +/- 0.2, and 7.3 +/- 1.7 ng/min, under basal conditions, respectively. These values increased significantly (p less than 0.05; n = 8) in response to a continuous stepwise stimulation at frequencies of 1, 3, and 10 Hz given at 3-min intervals during 9 min, reaching a maximum output of 4.6 +/- 0.9 (NPY-li), 240.2 +/- 50.2 (NE), and 1412.5 +/- 309.7 ng/min (E) at a frequency of 10 Hz. Burst electrical stimulation at 40 Hz for 1 s at 10-s intervals for a period of 10 min produced similar increases (p less than 0.05) in the release of NPY-li (4.8 +/- 1.0 ng/min, n = 8), NE (283.5 +/- 144.3 ng/min, n = 8), and E (1133.5 +/- 430.6 ng/min, n = 8). Adrenal NPY-li output was significantly correlated with adrenal NE output (r = 0.606; n = 24; p less than 0.05) and adrenal E output (r = 0.640; n = 24; p less than 0.05) in dogs receiving the burst stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Red blood cell catecholamine levels in normotensive and DOCA-salt hypertensive rats.

Under basal conditions in anesthetized rats, significant concentrations of free norepinephrine (NE), epinephrine (E), and dopamine (DA) were detected in red blood cell (RBC) lysate. These concentrations were not proportional to their respective plasma concentrations and thus RBC-to-plasma concentration ratios were different for each catecholamine (CA). DA was by far the most concentrated amine inside the RBC. An acute increase in plasma NE and E levels, induced by hemorrhagic hypotension in normotensive (NT) rats, did not result in any modification of the RBC CA content. However, chronic elevation of the NE plasma levels in bilaterally adrenalectomized rats and in deoxycorticosterone acetate (DOCA)-salt hypertensive rats (DOCA-salt HT) were associated with increased NE levels in the RBC. In addition, the large elevation in plasma E concentrations following hemorrhagic hypotension in DOCA-salt HT rats, as well as the greater plasma NE response to hypotension in adrenalectomized animals, were accompanied by increases in the respective RBC amine concentrations. During a steady-state intravenous infusion of tritiated NE, we observed a slow accumulation of radioactivity inside the RBC, indicating that CA can enter the RBC from the plasma. Moreover, catechol methyltransferase activity was measured in the cytosolic fraction of the RBC of both NT and DOCA-salt HT rats suggesting that, once inside the RBC, the catecholamines can be metabolized.

Free and conjugated catecholamines in plasma and red blood cells of normotensive and hypertensive patients.

Plasma free and conjugated norepinephrine levels were found to be significantly increased in patients with labile and sustained hypertension whereas epinephrine levels were normal in these patients. While free NE and E levels increased significantly during postural change, conjugated NE and E levels were not altered by this stimulus suggesting that conjugated NE levels could be an index of chronic rather than acute changes in the sympathetic tone. In hypertensive patients, plasma free dopamine levels increased during postural change and conjugated DA levels tended to be higher suggesting a dysfunction in the dopamine metabolism. Red blood cells were also found to contain free and conjugated CA. While conjugated CA levels in red blood cells (RBC) were equal or lower than in the plasma, free CA were found in larger concentrations than in the plasma. In hypertensive patients conjugated CA levels in RBC were similar to those found in normotensive subjects but free NE and E levels were significantly higher in hypertensive patients. These studies demonstrate various abnormalities in the metabolism of CA in hypertensive patients. Each of these could contribute to the maintenance of hypertension by an alteration of the biological expression of the sympathetic tone at the cellular level of these patients.

QT interval prolongation and increased plasma catecholamine levels in patients with mitral valve prolapse.

The heart rate corrected QT interval (QTc) and plasma catecholamine (CA) and norepinephrine (NE) levels were measured in 15 symptomatic patients with idiopathic mitral valve prolapse (MVP) and in 19 control subjects. MVP patients showed longer mean QTc and were divided into two groups: group A normal QTc (greater than 440 msec) and group B prolonged QTc (less than 440 msec). In supine resting conditions CA levels were as follows: group A 0.420 +/- 0.035 ng/ml and group B 0.619 +/- 0.104 ng/ml (p less than 0.05); both were greater than control values (0.348 +/- 0.017 ng/ml, p less than 0.005). NE levels were as follows: group A 0.350 +/- 0.031 ng/ml and group B 0.376 +/- 0.052 ng/ml (NS); both were greater than control values (0.242 +/- 0.025 ng/ml, (p less than 0.05). When a standing position was assumed, CA and NE levels increased significantly in all groups but this was most marked in group B as compared to control levels (CA: 1.039 +/- 0.123 ng/ml versus 0.625 +/- 0.037 ng/ml; NE: 0.737 +/- 0.076 ng/ml versus 0.504 +/- 0.031 ng/ml) (p less than 0.001 and p less than 0.05, respectively). Thus the longest QTc was observed in patients with MVP who had the highest levels of CA and NE, in both supine and standing positions. These data may account, in part, for the occurrence of severe ventricular arrhythmias in some patients with MVP and may offer a rationale for adrenergic blockade in that subset of patients with MVP and markedly prolonged QTc.

Comparative culture methods on 101 intravenous catheters. Routine, semiquantitative, and blood cultures.

Broth cultures and semiquantitative cultures (SQCs) were done on 101 intravenous (IV) catheters from 82 patients. Catheters were in place an average of ten days (range, one to 40 days). Twenty-eight catheters yielded 15 colonies or more to SQCs of transcutaneous catheter segments. Staphylococcus epidermidis was the most common microbial isolate found on 21 of the 28 catheters on SQC. Broth tip cultures, SQCs on tips and transcutaneous segments, qualitative blood cultures (QIBCs), and quantitative blood cultures (QnBCs) drawn via the catheters were significantly associated with peripheral bacteremia. The presence of systemic antimicrobials made no significant difference in SQC, QIBC, or QnBC positivity. With the exception of gross pus, local inflammation was not significantly associated with catheter infection. Local site care by a special team of nurses resulted in significantly fewer catheter infections than did care given by ward nurses.

Adaptive resistance to polymyxin in Pseudomonas aeruginosa due to an outer membrane impermeability mechanism.

The isolated outer membrane from cells of a Pseudomonas aeruginosa strain exhibiting adaptive resistance to polymyxin was not affected by polymyxin treatment, as monitored by electron microscopy of negatively stained preparations. This was in sharp contrast with extensive disruption by polymyxin of the outer membranes of the parent polymyxin-sensitive strain and the resistant strain following reversion to greater polymyxin sensitivity. The isolated cytoplasmic membrane of the polymyxin-resistant strain, on the other hand, remained sensitive to the disruptive effects of polymyxin treatment. The permeability characteristics of the resistant strains appear to be altered, as indicated by differences in minimal inhibitory concentrations for a variety of antibiotics between the polymyxin-sensitive and polymyxin-resistant strains. No evidence was found for a polymyxin-inactivating enzyme in osmotic shock fluid from the polymyxin-resistant strain. No evidence for a cytoplasmic membrane repair mechanism was found in the polymyxin-resistant strain. These observations suggest that the mechanism of adaptive polymyxin resistance in this model system is the alteration of the outer membrane so that it excludes polymyxin from reaching the still sensitive cytoplasmic membrane.

Circulating catecholamine levels in human and experimental hypertension.

The radiometric enzymatic technique of Coyle and Henry (J. Neurochem. 21: 61-67, 1973) was adapted to the measurement of serum catecholamines. This technique requires less time than other enzymatic techniques and is sensitive to quantities as small as 25 pg. In normotensive subjects lying supine for 20 minutes serum catecholamine levels averaged 0.218 ng/ml, with no obvious sex or age difference. Under these standardized conditions, the circulating catecholamine levels for a given individual are highly reproducible on different days over a period of several months. In 22 patients with essential hypertension, circulating levels were significantly higher, with an average of 0.370 ng/ml. More than 50% of the hypertensive patients had values greater than the highest value measured in normotensives. Systolic blood pressure and heart rate were significantly higher in the hypertensive group with elevated levels of circulating catecholamines than in the hypertensive group with normal levels. In one model of experimental hypertension, produced in the rat by administration of deoxycorticosterone acetate (DOCA) and saline for 4-8 weeks, serum catecholamines were significantly elevated. These findings suggest that the sympathetic system may play an important role in maintaining an elevated blood pressure in experimental hypertension and in a significant proportion of patients with essential hypertension.

Inhibition of Herpesvirus hominis replication by human interferon.

The effect of human interferon on single-cycle replication of Herpesvirus hominis type 1 (HV-1) and vesicular stomatitis virus (VSV) in human foreskin fibroblast cultures (HFF) was studied. After treatment of HFF cultures with low concentrations (58 U) of human interferon, a variable but statistically significant inhibition of HV-1 was observed. At higher concentrations (greater than 95 U) yield reduction of HV in interferon-treated cultures approached that of VSV. Preliminary data indicate that antiviral activity decays more rapidly for HV-1 than for VSV after removal of interferon from cultures.