Comparison of the Respiratory Resistomes and Microbiota in Children Receiving Short versus Standard Course Treatment for Community-Acquired Pneumonia.

Pediatric community-acquired pneumonia (CAP) is often treated with 10 days of antibiotics. Shorter treatment strategies may be effective and lead to less resistance. The impact of duration of treatment on the respiratory microbiome is unknown. Data are from children (n = 171), ages 6 to 71 months, enrolled in the SCOUT-CAP trial (NCT02891915). Children with CAP were randomized to a short (5 days) versus standard (10 days) beta-lactam treatment strategy. Throat swabs were collected at enrollment and the end of the study and used for shotgun metagenomic sequencing. The number of beta-lactam and multidrug efflux resistance genes per prokaryotic cell (RGPC) was significantly lower in children receiving the short compared to standard treatment strategy at the end of the study (Wilcoxon rank sum test, P < 0.05 for each). Wilcoxon effect sizes were small for beta-lactam (r: 0.15; 95% confidence interval [CI], 0.01 to 0.29) and medium for multidrug efflux RGPC (r: 0.23; 95% CI, 0.09 to 0.37). Analyses comparing the resistome at the beginning and end of the trial indicated that in contrast to the standard strategy group, the resistome significantly differed in children receiving the short course strategy. Relative abundances of commensals such as Neisseria subflava were higher in children receiving the standard strategy, and Prevotella species and Veillonella parvula were higher in children receiving the short course strategy. We conclude that children receiving 5 days of beta-lactam therapy for CAP had a significantly lower abundance of antibiotic resistance determinants than those receiving standard 10-day treatment. These data provide an additional rationale for reductions in antibiotic use when feasible. IMPORTANCE Antibiotic resistance is a major threat to public health. Treatment strategies involving shorter antibiotic courses have been proposed as a strategy to lower the potential for antibiotic resistance. We examined relationships between the duration of antibiotic treatment and its impact on resistance genes and bacteria in the respiratory microbiome using data from a randomized controlled trial of beta-lactam therapy for pediatric pneumonia. The randomized design provides reliable evidence of the effectiveness of interventions and minimizes the potential for confounding. Children receiving 5 days of therapy for pneumonia had a lower prevalence of two different types of resistance genes than did those receiving the 10-day treatment. Our data also suggest that children receiving longer durations of therapy have a greater abundance of antibiotic resistance genes for a longer period of time than do children receiving shorter durations of therapy. These data provide an additional rationale for reductions in antibiotic use.

First-in-Human Clinical Trial to Assess the Safety, Tolerability and Pharmacokinetics of Single Doses of NTM-1633, a Novel Mixture of Monoclonal Antibodies against Botulinum Toxin E.

Botulism is a rare, life-threatening paralytic disease caused by botulinum neurotoxin (BoNT). Available treatments including an equine antitoxin and human immune globulin are given postexposure and challenging to produce and administer. NTM-1633 is an equimolar mixture of 3 human IgG monoclonal antibodies, E1, E2, and E3, targeting BoNT serotype E (BoNT/E). This first-in-human study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of NTM-1633. This double-blind, single-center, placebo-controlled dose escalation study randomized 3 cohorts of healthy volunteers to receive a single intravenous dose of NTM-1633 (0.033, 0.165, or 0.330 mg/kg) or saline placebo. Safety monitoring included physical examinations, clinical laboratory studies, and vital signs. Blood sampling was performed at prespecified time points for PK and immunogenicity analyses. Twenty-four subjects received study product (18 NTM-1633; 6 placebo), and no deaths were reported. An unrelated serious adverse event was reported in a placebo subject. Adverse events in the NTM-1633 groups were generally mild and similar in frequency and severity to the placebo group, and no safety signal was identified. NTM-1633 has a favorable PK profile with a half-life >10 days for the 0.330 mg/kg dose and an approximately linear relationship with respect to maximum concentration and area under the concentration-time curve (AUC0→t). NTM-1633 also demonstrated low immunogenicity. NTM-1633 is well tolerated at the administered doses. The favorable safety, PK, and immunogenicity profile supports further development as a treatment for BoNT/E intoxication and postexposure prophylaxis.

Safety, Tolerability, and Pharmacokinetics of NTM-1632, a Novel Mixture of Three Monoclonal Antibodies against Botulinum Toxin B.

Botulism is a rare, life-threatening paralytic disease caused by Clostridium botulinum neurotoxin (BoNT). Available treatments, including an equine antitoxin and human immune globulin, are given postexposure and challenging to produce and administer. NTM-1632 is an equimolar mixture of 3 human IgG monoclonal antibodies, B1, B2, and B3, targeting BoNT serotype B (BoNT/B). This first-in-human study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of NTM-1632. This double-blind, single-center, placebo-controlled dose escalation study randomized 3 cohorts of healthy volunteers to receive a single intravenous dose of NTM-1632 (0.033, 0.165, or 0.330 mg/kg) or saline placebo. Safety monitoring included physical examinations, clinical laboratory studies, and vital signs. Blood sampling was performed at prespecified time points for PK and immunogenicity analyses. Twenty-four subjects received study product (18 NTM-1632; 6 placebo), and no deaths or serious adverse events were reported. Adverse events in the NTM-1632 groups were generally mild and similar in frequency and severity to the placebo group, and no safety signal was identified. NTM-1632 has a favorable PK profile with a half-life of >20 days for the 0.330-mg/kg dose and an approximately linear relationship with respect to maximum concentration and area under the concentration-time curve (AUC0→t). NTM-1632 demonstrated low immunogenicity with only a few treatment-emergent antidrug antibody responses in the low and middle dosing groups and none at the highest dose. NTM-1632 is well tolerated at the administered doses. The favorable safety, PK, and immunogenicity profile of NTM-1632 supports further clinical development as a treatment for BoNT/B intoxication and postexposure prophylaxis. (This study has been registered at ClinicalTrials.gov under identifier NCT02779140.).

A Preliminary Study: Efficacy of Mindfulness-Based Cognitive Therapy versus Sertraline as First-line Treatments for Major Depressive Disorder.

Major depressive disorder (MDD) is the leading cause of disability in the developed world, yet broadly effective treatments remain elusive. The primary aim of this pilot study was to investigate the efficacy of Mindfulness-Based Cognitive Therapy (MBCT) monotherapy, compared to sertraline monotherapy, for patients with acute MDD. This open-label, nonrandomized controlled trial examined a MBCT cohort (N=23) recruited to match the gender, age, and depression severity of a depressed control group (N=20) that completed 8 weeks of monotherapy with the antidepressant sertraline. The 17-item clinician-rated Hamilton Depression Severity Rating Scale (HAMD-17) was the primary outcome measure of depression to assess overall change after 8 weeks and rates of response and remission. The 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16) was the secondary outcome measure to further assess depression severity. Both cohorts were demographically similar and showed significant improvement in depression ratings. No difference was found in the degree of change in HAMD-17 scores (t(34) = 1.42, p = .165) between groups. Secondary analysis showed statistically significant differences in mean scores of the QIDS-SR16 (t (32) = 4.39, p < 0.0001), with the MCBT group showing greater mean improvement. This study was limited by the small sample size and non-randomized, non-blinded design. Preliminary findings suggest that an 8-week course of MBCT monotherapy may be effective in treating MDD and a viable alternative to antidepressant medication. Greater changes in the self-rated QIDS-SR16 for the MBCT cohort raise the possibility that patients derive additional subjective benefit from enhanced self-efficacy skills.

Mindfulness-based cognitive therapy: theory and practice.

Mindfulness-based cognitive therapy (MBCT) incorporates elements of cognitive-behavioural therapy with mindfulness-based stress reduction into an 8-session group program. Initially conceived as an intervention for relapse prevention in people with recurrent depression, it has since been applied to various psychiatric conditions. Our paper aims to briefly describe MBCT and its putative mechanisms of action, and to review the current findings about the use of MBCT in people with mood and anxiety disorders. The therapeutic stance of MBCT focuses on encouraging patients to adopt a new way of being and relating to their thoughts and feelings, while placing little emphasis on altering or challenging specific cognitions. Preliminary functional neuroimaging studies are consistent with an account of mindfulness improving emotional regulation by enhancing cortical regulation of limbic circuits and attentional control. Research findings from several randomized controlled trials suggest that MBCT is a useful intervention for relapse prevention in patients with recurrent depression, with efficacy that may be similar to maintenance antidepressants. Preliminary studies indicate MBCT also shows promise in the treatment of active depression, including treatment-resistant depression. Pilot studies have also evaluated MBCT in bipolar disorder and anxiety disorders. Patient and clinician resources for further information on mindfulness and MBCT are provided.

Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia.

Protease-activated receptor (PAR(2)) is expressed by nociceptive neurons and activated during inflammation by proteases from mast cells, the intestinal lumen, and the circulation. Agonists of PAR(2) cause hyperexcitability of intestinal sensory neurons and hyperalgesia to distensive stimuli by unknown mechanisms. We evaluated the role of the transient receptor potential vanilloid 4 (TRPV4) in PAR(2)-induced mechanical hyperalgesia of the mouse colon. Colonic sensory neurons, identified by retrograde tracing, expressed immunoreactive TRPV4, PAR(2), and calcitonin gene-related peptide and are thus implicated in nociception. To assess nociception, visceromotor responses (VMR) to colorectal distension (CRD) were measured by electromyography of abdominal muscles. In TRPV4(+/+) mice, intraluminal PAR(2) activating peptide (PAR(2)-AP) exacerbated VMR to graded CRD from 6-24 h, indicative of mechanical hyperalgesia. PAR(2)-induced hyperalgesia was not observed in TRPV4(-/-) mice. PAR(2)-AP evoked discharge of action potentials from colonic afferent neurons in TRPV4(+/+) mice, but not from TRPV4(-/-) mice. The TRPV4 agonists 5',6'-epoxyeicosatrienoic acid and 4alpha-phorbol 12,13-didecanoate stimulated discharge of action potentials in colonic afferent fibers and enhanced current responses recorded from retrogradely labeled colonic dorsal root ganglia neurons, confirming expression of functional TRPV4. PAR(2)-AP enhanced these responses, indicating sensitization of TRPV4. Thus TRPV4 is expressed by primary spinal afferent neurons innervating the colon. Activation of PAR(2) increases currents in these neurons, evokes discharge of action potentials from colonic afferent fibers, and induces mechanical hyperalgesia. These responses require the presence of functional TRPV4. Therefore, TRPV4 is required for PAR(2)-induced mechanical hyperalgesia and excitation of colonic afferent neurons.

Diffuse alterations in synaptic protein expression following focal traumatic brain injury in the immature rat.

INTRODUCTION: The mechanisms responsible for cognitive decline after traumatic brain injury (TBI) in pediatric patients are poorly understood. The present study examined the potential role of synaptic alterations in this process by using an animal model of immature head injury to define the impact of TBI on expression of the synaptic protein, synaptophysin. MATERIALS AND METHODS: After craniotomy, TBI was induced in postnatal day 17 (PND17) rats using controlled cortical impact delivered to the left hemisphere. NeuN, a neuronal marker, and synaptophysin expression were examined 1 day, 1 week, and 1 month after injury by immunohistochemistry and immunoblotting. RESULTS: There were significant decreases in both NeuN and synaptophysin after 1 day and 1 week but not 1 month after injury within the hippocampus and neocortex adjacent to the impact site compared to sham-injured controls. The decrease in synaptophysin and NeuN was also noted in the contralateral hippocampus by 1 day after injury and in the contralateral neocortex by 1 week, indicating that changes in protein expression were not solely localized to the injury site but occurred in more distant regions as well. DISCUSSION: In conclusion, the decrease and recovery in synaptophysin parallel the cognitive changes that occur after experimental TBI in the PND17 rat, which suggests that changes in this protein may contribute to cognitive declines after injury. The results also suggest that, in spite of the focal nature of the impact, diffuse alterations in protein expression can occur after immature TBI and may contribute to the subsequent cognitive dysfunction.

Tuberculosis knowledge and attitudes among physicians who treat young children in North Carolina, USA.

SETTING: North Carolina, USA. OBJECTIVE: To understand physicians' knowledge and attitudes toward the treatment of young children with latent tuberculosis infection (LTBI) in a low-incidence region. DESIGN: Cross-sectional survey of 525 pediatricians and 525 family practitioners in North Carolina. RESULTS: Of 1050 surveys mailed, 149 (14%) were returned. In the previous year, 96% of responding physicians had treated children who had emigrated from a tuberculosis (TB) endemic country. During the last 2 years, 84% of physicians had not diagnosed any young children with TB disease, and 46% had not treated any young children with LTBI. Most (83%) physicians routinely placed tuberculin skin tests (TSTs), and 26% reported placing > 10 TSTs per month. Experience in treating children with LTBI was the only predictor of TB knowledge. Physicians were particularly confused about two issues: 1) TST among bacille Calmette-Guérin (BCG) vaccinated children and 2) treatment of young children with recent exposure to an adult with infectious TB. CONCLUSIONS: Knowledge of important issues related to management of LTBI in children aged < 5 years was limited among physicians in an area with relatively low TB incidence. Creative methods must be developed to help physicians in low-incidence areas to appropriately diagnose and treat LTBI among young children.

Propylthiouracil-associated liver failure presenting as probable autoimmune hepatitis in a child with Graves' disease.

This case describes a young girl with Graves' disease, who presented with fulminant hepatic failure 9 months into propylthiouracil (PTU) therapy. Her clinical presentation was consistent with 'probable autoimmune hepatitis,' as defined by the International Autoimmune Hepatitis Group scoring system. Despite discontinuation of PTU and high-dose steroid therapy, she required liver transplantation. Subsequent pathology could not definitively rule out autoimmune hepatitis. PTU is an important cause of drug-related liver failure in children, and clinicians should be mindful that it is frequently used in patients who already have an underlying risk of autoimmune liver disease.

Cell surface tumor endothelial markers are conserved in mice and humans.

We recently identified genes encoding tumor endothelial markers (TEMs) that displayed elevated expression during tumor angiogenesis. From both biological and clinical points of view, TEMs associated with the cell surface membrane are of particular interest. Accordingly, we have further characterized four such genes, TEM1, TEM5, TEM7, and TEM8, all of which contain putative transmembrane domains. TEM5 appears to be a seven-pass transmembrane receptor, whereas TEM1, TEM7, and TEM8 span the membrane once. We identified mouse counterparts of each of these genes, designated mTEM1, mTEM5, mTEM7, and mTEM8. Examination of these mTEMs in mouse tumors, embryos, and adult tissues demonstrated that three of them (mTEM1, mTEM5, and mTEM8) were abundantly expressed in tumor vessels as well as in the vasculature of the developing embryo. Importantly, expression of these mTEMs in normal adult mouse tissues was either undetectable or detected only in a small fraction of the vessels. These results demonstrate conservation of human and mouse tumor angiogenesis at the molecular level and support the idea that tumor angiogenesis largely reflects normal physiological neovasculaturization. The coordinate expression of TEM1, TEM5, and TEM8 on tumor endothelium in humans and mice makes these genes attractive targets for the development of antiangiogenic therapies.

Barriers to universal prenatal HIV testing in 4 US locations in 1997.

OBJECTIVES: We determined rates of prenatal HIV testing and investigated barriers to testing. METHODS: We surveyed 1362 representative parturient women from 7 hospitals in 4 locations of the United States. RESULTS: Overall, 89.9% of women reported being offered HIV testing and 69.6% reported being tested. Proportions of women not offered testing differed by location (range = 5.2%-16.3%), as did proportions not tested (range = 12.2%-54.4%). Among women who perceived that their clinicians had not recommended testing, 41.7% were tested, compared with 92.8% of women who perceived a strong recommendation (P < .05). Private insurance for prenatal care was also associated with not being tested. Women gave multiple reasons for not being tested, most commonly not being at risk, having been tested recently, and the test's not being offered or recommended, cited by 55.3%, 39.1% and 11.1% of women, respectively. CONCLUSIONS: Although most parturient women were offered a prenatal HIV test and got tested, testing proportions did not reach national goals and differed significantly by location and payment status. Concern about testing consequences was not a major barrier. Perception of clinicians' recommendations strongly influenced testing. Changing provider practices will be essential to implementing universal prenatal HIV testing.

Partial uptake of varicella vaccine and the epidemiological effect on varicella disease in 11 day-care centers in North Carolina.

BACKGROUND: The increasing use of varicella vaccine in children attending day care has rapidly decreased the incidence of wild-type varicella disease. The herd immunity noted is significant and will have an effect on the epidemiology of natural varicella. OBJECTIVE: To monitor the change in varicella incidence in day-care attendees after the licensure of varicella vaccine. DESIGN: A prospective observational cohort study design. SETTING: Eleven private day-care centers and preschools in North Carolina participated in the study from January 1, 1995, through December 31, 1999. PARTICIPANTS: All children in the 11 centers were eligible for participation. Some participated more actively, supplying information on a regular basis. Others participated passively. Day-care personnel provided information about all cases of varicella. INTERVENTIONS: None. MAIN OUTCOME VARIABLES: The change in the incidence of varicella disease was documented as the use of varicella vaccine increased. RESULTS: Varicella vaccine coverage increased substantially from 4.4% in 1995 to 63.1% in December 1999. The vaccination rate accelerated dramatically in 1996 and 1997, leveled off in 1998, and rose again in 1999. Cumulative varicella incidence decreased from 16.74 cases per 1000 person-months in July 1996 to 1.53 cases per 1000 person-months in December 1999 in unvaccinated children. CONCLUSIONS: The varicella vaccination rate continued to increase slowly in the day-care population after an initial rapid uptake. The decrease in varicella disease is greater than the increase in varicella vaccination. This herd effect is welcome and even apparent in the unvaccinated children younger than 1 year.

New mothers' knowledge and attitudes about perinatal human immunodeficiency virus infection.

OBJECTIVES: To assess new mothers' attitudes toward perinatal human immunodeficiency virus (HIV) testing, their knowledge about perinatal HIV, and their trust of government and scientists. METHODS: In a cross-sectional survey of 1362 postpartum women at four United States locations in 1997, a standardized interview was administered to new mothers 24-48 hours postpartum to determine their HIV test acceptance, attitudes, and knowledge. RESULTS: Seventy-five percent of women who were offered HIV tests reported being tested. Although 95% of women were aware of perinatal HIV transmission, only 60% knew that HIV can be transmitted through breast-feeding, and only 51% knew of medication to prevent perinatal transmission. Eighty-four percent of women thought that all pregnant women should be tested for HIV, and 60% thought that prenatal HIV testing should be legally mandated. Twenty percent of women indicated mistrust of government and scientists regarding origins of HIV and potential cures for AIDS. Knowledge about perinatal transmission was unrelated to receipt of prenatal HIV tests. When other factors were controlled for, mistrust was not significantly associated with getting tested. CONCLUSION: Incomplete knowledge of prevention of perinatal HIV transmission and mistrust were prevalent among new mothers. Knowledge deficits or mistrust did not appear to reduce reported prenatal test rates, but our data suggest that future public health efforts need to educate women about methods of preventing perinatal HIV transmission and at enhancing their trust in the public health system.

Infant birth weight among women with or at high risk for HIV infection: the impact of clinical, behavioral, psychosocial, and demographic factors.

The purpose of these analyses was to provide a prospective examination of the impact of HIV on birth weight using clinical, behavioral, psychosocial, and demographic correlates. HIV-positive (n = 319) and HIV-negative (n = 220) pregnant women matched for HIV risk factors (i.e., drug use and sexual risk behaviors) were interviewed during the 3rd trimester of pregnancy and 6 weeks postpartum. Medical chart reviews were also conducted for the HIV-seropositive pregnant women to verify pregnancy-related and birth outcome data. In a logistic regression analysis, model chi2(9, N = 518) = 124.8, p < .001, controlling for parity and gestational age, women who were HIV seropositive were 2.6 times more likely to have an infant with low birth weight. In addition, Black women and those who did not live with their partners were more than 2 times as likely to have infants with low birth weight, and those who smoked were 3.2 times more likely to have infants with low birth weight. Knowing that women with HIV, those who are Black, and those not living with a partner are at highest risk for adverse birth outcomes can help those in prenatal clinics and HIV specialty clinics to target resources and develop prevention interventions. This is particularly important for women with HIV because birth weight is associated with risk of HIV transmission from mother to child.

Acceptance of HIV testing during prenatal care. Perinatal Guidelines Evaluation Project.

OBJECTIVE: The purpose of this study was to assess the factors associated with acceptance of HIV testing during pregnancy on the part of women receiving prenatal care at public clinics. METHODS: Trained interviewers recruited and interviewed 1,357 women receiving prenatal care at clinics in Florida, Connecticut, and New York City. RESULTS: Eighty-six percent of participants reported having been tested or having signed a consent form to be tested. Acceptance of testing was found to be related to strong beliefs about the benefits of testing, knowledge about vertical transmission, perceived provider endorsement of testing, and social support. Women who declined testing said they did so because they did not perceive themselves to be at risk for HIV (21%) or they faced administrative difficulties (16%) with some aspect of the testing process (for example, scheduling, limited availability of pre-test counselors). CONCLUSIONS: Acceptance rates can be increased when women understand the modes of vertical transmission and the role of medication regimens in preventing transmission; believe that prenatal identification of HIV can promote the health of mother and child; and perceive their providers as strongly endorsing testing. These points can be woven into a brief pre-test counseling message and made a routine component of prenatal care.

Postlicensure study of varicella vaccine effectiveness in a day-care setting.

BACKGROUND: Varicella vaccine has been licensed for use in the United States since the spring of 1995. The acceptance of the vaccine and its effect on varicella incidence in children is important. AIM: To document the effectiveness of the varicella vaccine in children attending day care in 11 centers in North Carolina. METHODS: A dynamic cohort study design was used in 11 day-care centers in North Carolina. Multiple cross-sectional evaluations were performed and children were noted to be vaccinated or not and diseased or not. Vaccine effectiveness was estimated by comparing the varicella attack rate in the vaccinated with the varicella attack rate in the unvaccinated. Person time was used as the denominator for all calculations. RESULTS: During the study period February 1, 1996, to September 1, 1997, 134 cases of varicella occurred in the unvaccinated and 11 cases occurred in the vaccinated children. The attack rates in the vaccinated and unvaccinated were 2.49 and 14.66, respectively, for an overall vaccine effectiveness of 83% for mild/moderate disease. CONCLUSIONS: In the day-care setting varicella vaccine demonstrated benefit in preventing and modifying wild-type varicella disease.

Characterization of MAD2B and other mitotic spindle checkpoint genes.

Aneuploidy is a characteristic of the majority of human cancers, and recent work has suggested that mitotic checkpoint defects play a role in its development. To further explore this issue, we isolated a novel human gene, MAD2B (MAD2L2), which is homologous to the spindle checkpoint gene MAD2 (MAD2L1). We determined the chromosomal localization of it and other spindle checkpoint genes, including MAD1L1, MAD2, BUB3, TTK (MPS1L1), and CDC20. In addition, we resolved the genomic intron-exon structure of the human BUB1 gene. We then searched for mutations in these genes in a panel of 19 aneuploid colorectal tumors. No new mutations were identified, suggesting that genes yet to be discovered are responsible for most of the checkpoint defects observed in aneuploid cancers.

Concurrent administration of inactivated hepatitis A vaccine with immune globulin in healthy adults.

301 healthy adult volunteers were randomized to one of three treatment groups: inactivated hepatitis A vaccine alone; inactivated hepatitis A vaccine with immune globulin (Ig) concurrently; or Ig alone. The first two treatment groups received a second dose of hepatitis A vaccine at week 24. Anti-HAV was measured 4, 8, 12, 24 and 28 weeks after the primary immunization. When comparing subjects receiving inactivated hepatitis A vaccine alone to those receiving vaccine and Ig, the seropositivity rates were not significantly different at 4, 8, 12 and 28 weeks, but at week 24 the seropositivity rate was lower in the group receiving both vaccine and Ig compared to the group receiving vaccine alone (92.0% compared to 97.0%). At weeks 8, 12 and 24 the geometric mean titers (GMTs) were significantly lower for subjects receiving both vaccine and Ig. The GMTs were not significantly different after the second dose of vaccine. At all time points, the lower serum antibody concentrations observed in subjects receiving both inactivated hepatitis A vaccine and Ig were nevertheless substantially higher than the cutoff for assay seropositivity and much higher than after Ig alone; these differences are therefore clinically insignificant.