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.).

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.

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.

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.

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.

Post-transcriptional silencing of RET occurs, but is not required, during raf-1 mediated differentiation of medullary thyroid carcinoma cells.

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor of the calcitonin secreting thyroid C-cells. Somatic and germline mutations in the RET proto-oncogene are associated with sporadic and inherited cases of MTC, respectively. The human MTC cell line, TT, can be differentiated by activated raf-1. This differentiation is characterized, in part, by down-regulation of the RET proto-oncogene. We now show that raf-1 induction is followed by activation of the downstream kinases MEK1/2 and ERK1/2 and that differentiation is dependent on activation of MEK1/2. The concurrent down-regulation of RET appears to involve altered nuclear compartmentalization and transport of RET mRNA. Although RET is down-regulated during raf-1 mediated differentiation, overexpression of activated RET alleles which resist down-regulation does not alter the raf-1 mediated differentiation response. These data suggest that RET down-regulation is associated with, but not required, for raf-1 mediated MTC cell differentiation and that the raf-1 signal transduction pathway plays a dominant role in promoting MTC cell differentiation.

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.

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.

Immunogenicity of Haemophilus b conjugate vaccine (meningococcal protein conjugate) in children with prior invasive Haemophilus influenzae type b disease.

Children younger than 2 years of age with previous invasive Haemophilus influenzae (Hib) type b disease may not develop protective antibodies to antigens of Hib and may be at risk of developing a second episode of Hib disease. Twenty-three children with prior Hib disease were immunized with Haemophilus b conjugate vaccine (meningococcal protein conjugate). Children 12 to 24 months of age were given one dose of vaccine and children younger than 12 months of age were given 2 doses 2 months apart. Antibody to the polysaccharide capsule of Hib (PRP) was measured by radioimmunoassay. Eighteen children had preimmunization serum antibody concentrations less than 0.150 micrograms/ml. All 18 children responded with greater than 0.150 micrograms/ml of antibody after a single dose of vaccine. Only 1 of the 23 children had a preimmunization serum antibody concentration greater than 1.000 micrograms/ml. Seventeen children ultimately responded with greater than 1.000 micrograms/ml of antibody (P less than 0.0001), concentrations of antibody thought to correlate with protection. Haemophilus b conjugate vaccine (meningococcal protein conjugate) is immunogenic in children with invasive Hib disease. Children younger than 2 years of age with invasive Hib disease should be subsequently immunized with a Hib conjugate vaccine.

Maternal acceptance of voluntary human immunodeficiency virus antibody testing during the newborn period with the Guthrie card.

In order to provide the opportunity for women delivering newborns to have human immunodeficiency virus (HIV) testing we piloted a hospital-based voluntary HIV testing program during the newborn period using the Guthrie card. During the study period 789 women were offered newborn HIV antibody testing. Test acceptance during the newborn period (61.0%) was comparable to that reported for the prenatal period (60.6%). Overall 77.4% of women were tested in the newborn period or reported being tested in the prenatal period. Prenatal test acceptance best predicted newborn HIV test acceptance (odds ratio, 3.37; 95% confidence interval, 2.40 to 4.74). When compared to HIV testing during the newborn period prenatal HIV testing is preferable because it enables the recognition of HIV infection early during pregnancy and allows the mother the option to elect zidovudine therapy and potentially prevent infection in her newborn. However, when prenatal HIV testing is not routinely made available or cannot be assured, women should be offered the opportunity to be tested during the newborn period.

Over five-year follow-up of Oka/Merck varicella vaccine recipients in 465 infants and adolescents.

A total of 465 healthy infants and adolescents ages 12 months to 17 years without a known history of varicella or recent exposure to varicella-zoster virus VZV were immunized with live attenuated Oka/Merck varicella vaccine from November, 1984, through April, 1989. The vaccine administered was from 1 of 7 production lots containing from 950 to 3265 plaque-forming units and was well-tolerated with few side effects. The seroconversion rate for seronegative subjects was 94.6% (403 of 426). This varied by lot from 85% (950 plaque-forming units) to 100% (3010 and 3265 plaque-forming units). Breakthrough disease after exposure to varicella in seroconverters during 5 to 10 years of follow-up was 18.6% (75 of 403). The breakthrough disease was characterized by a maculopapular rash with a median of 35 lesions, most of which were macules. Breakthrough disease lasted a median of 5 days and the median temperature was 99 degrees F; 65.3% (49 of 75) of subjects were afebrile and 2.7% (2 of 75) of subjects had temperatures of > 102.9 degrees F. Varicella vaccine provides excellent (94.6%) seroconversion, and most children who developed breakthrough disease (18.6%) experienced a modified, milder form of illness than has been observed with natural varicella in unvaccinated subjects.

Differentiation of medullary thyroid cancer by C-Raf-1 silences expression of the neural transcription factor human achaete-scute homolog-1.

BACKGROUND: Human achaete-scute homolog-1 (hASH1), a fetal neural transcription factor, is highly expressed in neuroendocrine tumors such as medullary thyroid cancer (MTC). Although hASH1 probably plays a part in the growth and development of these tumors, its precise role and mechanism are unknown. METHODS: To further elucidate the function and regulation of hASH1 in neuroendocrine tumor differentiation, we used a model of MTC tumor differentiation mediated by the ras/raf-1 signaling pathway. The MTC TT cells alone or transduced with a beta-estradiol activatable raf-1 construct (TT: delta Raf-1:ER) were treated with beta-estradiol or carrier. Northern analysis and nuclear run-off assays were performed to determine the hASH1 messenger RNA (mRNA) levels and transcription rate, respectively. RESULTS: The TT: delta Raf-1:ER cells treated with beta-estradiol underwent marked biochemical and morphologic changes, including cell rounding, increase in calcitonin transcription, loss of RET proto-oncogene expression, and cessation of cell growth. During this differentiation process expression of hASH1 mRNA was silenced. Nuclear run-off experiments revealed that this decrease in steady-state hASH1 mRNA by raf-1 activation resulted predominantly from transcriptional inhibition. CONCLUSIONS: Silencing of hASH1 in parallel with loss of RET is associated with development of a mature C-cell differentiation pattern. Mechanisms leading to transcriptional silencing of hASH1 may be crucial in regulating the proliferative capacity or differentiation status of MTC. Downstream targets of hASH1 could play a role in C-cell proliferation and progression to MTC.

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.