HCV genotype 4, 5 and 6: Distribution of viral subtypes and sustained virologic response rates in clinical trials of approved direct-acting antiviral regimens.

Multiple direct-acting antiviral (DAA)-based regimens are now available for all hepatitis C virus (HCV) genotypes (GTs). Because HCV GT 4, 5 and 6 are less common in the United States (US) and worldwide, relatively small numbers of participants with these GTs were evaluated in individual clinical trials. To provide a comprehensive description of subtype diversity and treatment outcomes in clinical trials for these less common GTs, we analysed data from 744 participants with HCV GT4 (n = 573), GT5 (n = 81), or GT6 (n = 90) across 18 clinical trials of DAA regimens. These data are from US New Drug Applications submitted between 2014 and 2017, and our analyses included only approved regimens. Excluding unresolved or mixed subtypes, the distribution of reported GT4 subtypes was 49% 4a, 31% 4d and 16% for one of 14 other subtypes. The distribution of GT6 subtypes was 39% 6a, 27% 6e, 8% 6 L and 23% for one of 11 other subtypes. Across approved regimens, sustained virologic response rates 12 weeks post-treatment (SVR12) for GT 4, 5 and 6 ranged from 91% to 100%, 93% to 97% and 96% to 100%, respectively. SVR12 by GT4 subtype ranged from 96% to 100% for 4a and 81% to 100% for 4d. Virologic failures occurred in GT 4a, 4b, 4d and 4r. For GT6, SVR12 was 100% for all subtypes except 6 L, for which 1 of 7 participants experienced virologic failure. To our knowledge, this is the largest compilation of HCV GT 4, 5 or 6 clinical trial data. These analyses may be useful for clinicians treating HCV GT 4, 5 or 6.

Noninvasive ventilation during gastrostomy tube placement in patients with severe duchenne muscular dystrophy: case reports and review of the literature.

Individuals with Duchenne muscular dystrophy may benefit from gastrostomy tube feeding due to progressive dysphagia and malnutrition. However, due to their severely impaired pulmonary function, these individuals are at risk of severe complications when they are sedated or undergo anesthesia for the procedure. We previously described a technique of noninvasive positive pressure ventilation to provide respiratory support during gastrostomy tube placement in such patients, but this technique had risks and limitations. In this case report, we examine two alternative techniques we used to provide respiratory support successfully to patients with severe muscular dystrophy and malnutrition who underwent percutaneous endoscopic gastrostomy tube placement. We then review the literature and discuss the potential benefits, risks, and limitations of the above techniques and of other options for gastrostomy placement in people with severe muscular dystrophy.

The use of colposcopy in assessing vaginal irritation in research.

Since the early 1990s, colposcopy of the vagina and cervix has been used in the development of vaginal products in order to detect epithelial changes that may increase the likelihood of HIV or acquisition of other sexually transmitted diseases. As part of a continued effort to examine and define the role of colposcopy in a research setting, the Contraceptive Research and Development Program (CONRAD) and the International Working Group on Microbicides (IWGM), in association with the United Nations Program for AIDS (UNAIDS) sponsored a conference entitled, 'The Use of Colposcopy in Assessing Vaginal Irritation in Research', held in Washington, DC in January 1999. This is a report of that conference. The World Health Organization's colposcopy procedure and nomenclature, published in 1995, were reviewed and changes were recommended. The revised procedure involves colposcopic examination of the external genitalia, naked eye examination of the cervix, fornices, and vaginal walls, followed by lavage and colposcopic examination of those areas, and sampling as appropriate for microscopic examination. Revised nomenclature replaces the terms used for findings with descriptions of what is actually seen. Digital video imaging and testing for inflammatory markers may be adjuncts to colposcopy and should be further studied. Other areas requiring additional research include the natural history of colposcopic changes, factors other than product use that may affect colposcopic findings, the clinical significance of findings, and the procedure which best assesses these findings.

Chronic hypoxia increases beta-adrenergic receptor density in the lungs of young and old rats.

To test the hypothesis that the ability to regulate beta-adrenergic receptor (BAR) density in response to chronic hypoxic stress is impaired by aging, we measured BAR density in the lungs of young (age 3 months) and aged (age 20 months) rats exposed to hypobaric hypoxia (1/2 atm) for 3 weeks. BAR density increased by 63% in the lungs of both young and aged rats exposed to chronic hypoxia. Lung BAR density was unaffected by aging, independent of hypoxic conditions. We conclude that the ability to respond to chronic hypoxic stress with increased lung BAR density is unaffected by aging in rats.

Noninvasive ventilation during percutaneous gastrostomy placement in Duchenne muscular dystrophy.

Noninvasive positive pressure ventilation (NPPV) is used for respiratory support in a number of diseases causing acute or chronic respiratory failure. We describe a novel use of NPPV to provide respiratory support during sedation for percutaneous placement of a gastrostomy tube in a patient with Duchenne muscular dystrophy (DMD). The patient had severe respiratory insufficiency, progressive dysphagia, and undernutrition. In addition to the case in this report, we have used NPPV to provide respiratory support to DMD patients during five other gastrointestinal endoscopies without complication. The technique is highly labor intensive and requires physicians and respiratory therapists familiar with NPPV. The primary risk associated with this technique is lack of definitive airway protection during the procedure, which must be balanced against the risks of intubation in an anesthetized patient with neuromuscular disease. The potential benefit to selected patients is substantial, such as initiation of gastrostomy tube feeding in our patient, with subsequent improvement in his quality of life and nutritional status.

Persistent pulmonary consolidation treated with intrapulmonary percussive ventilation: a preliminary report.

Intrapulmonary percussive ventilation (IPV) is a novel form of chest physiotherapy delivered by a percussive pneumatic device (IPV, Percussionaire, Sand Point, ID). There are few published reports about the use of IPV for diseases other than cystic fibrosis. We report our experience with three pediatric patients and one adult patient with persistent pulmonary consolidation refractory to conventional therapies. Three of the four patients had neuromuscular disease; one patient had segmental atelectasis due to aspiration. Three of the four patients showed clinical and radiographic improvement within 48 hours of starting IPV. The fourth patient experienced brief episodes of third-degree atrioventricular block, hypoxemia, and bradycardia during two IPV treatments. IPV was safely restarted and he slowly improved. We conclude that while IPV requires further clinical evaluation, it appears to be a safe and effective therapy for selected patients. However, close observation is essential during and after IPV treatments, especially in patients who have difficulty mobilizing or expectorating sputum.

Pediatric noninvasive nasal ventilation.

Noninvasive nasal ventilation is an effective but underutilized method of chronic respiratory support for patients with respiratory insufficiency due to neuromuscular disease. Noninvasive nasal ventilation corrects nocturnal hypoxia and hypercapnia, resolving symptoms of chronic alveolar hypoventilation. Noninvasive nasal ventilation can allow selected patients with acute respiratory failure to avoid intubation and it can facilitate endotracheal extubation. Practical guidelines and the rationale for pediatric noninvasive nasal ventilation therapy will be discussed in this review.

Management of the respiratory complications of neuromuscular diseases in the pediatric intensive care unit.

Pediatric neuromuscular diseases such as Duchenne muscular dystrophy and spinal muscular atrophy cause pulmonary compromise. In severely affected patients, upper respiratory tract infections exacerbate lower respiratory tract secretion retention, with the potential for pneumonia, pulmonary atelectasis, and respiratory failure. In the pediatric intensive care unit, effective treatment includes noninvasive positive pressure ventilation and manual and mechanical mucus clearance techniques. A practical approach to commonly encountered respiratory complications in pediatric neuromuscular diseases is presented in this review.

Treatment of type I spinal muscular atrophy with noninvasive ventilation and gastrostomy feeding.

Type I spinal muscular atrophy (SMA) is a rapidly progressive, degenerative neuromuscular disease of infancy. In severe SMA, weakness, hypotonia, and bulbar involvement lead to progressive respiratory insufficiency and swallowing dysfunction, which are frequently complicated by aspirations. There are few studies reported in the literature that address the respiratory management of type I SMA. This article reports the results of treating four patients with infantile SMA with noninvasive positive pressure ventilation and gastrostomy feeding. All patients had gastroesophageal reflux disease, which was managed medically. Despite these therapies, survival was only 1 to 3.5 months after presenting with severe aspirations. The treatment strategy, which can be effective in less rapidly progressive neuromuscular diseases, did not alter the very poor prognosis of type I SMA. The treatment options are reviewed, and a strategy designed to optimize quality of life for infants with this fatal disease is presented.

Effect of dexamethasone on lymphocyte subpopulations in premature infants with bronchopulmonary dysplasia.

OBJECTIVE: This study was designed to determine the effect of dexamethasone treatment on peripheral blood lymphocyte counts and subpopulations in premature infants with bronchopulmonary dysplasia (BPD). STUDY DESIGN: Peripheral blood lymphocyte subpopulations in 12 premature infants with BPD were analyzed before treatment with a 6-week course of dexamethasone (day 0), on days 3 and 10 of treatment, and 2 weeks after discontinuing dexamethasone therapy (day 56). Lymphocyte immunophenotypes were determined using direct two-color immunofluorescent staining followed by flow cytometry. RESULTS: The percentage of lymphocytes was significantly lower on days 3 (17.55 +/- 2.55) and 10 (20 +/- 11.8) of dexamethasone therapy compared with before (30.36 +/- 6.41) or after treatment. The percentage of T cells was significantly lower on days 3 and 10 of dexamethasone therapy (mean +/- SEM; 58.09 +/- 1.93 and 60.09 +/- 2.47, respectively) compared with before (67.09 +/- 4.24) or after treatment. The absolute number of T cells was significantly lower on day 10 of therapy. The percentage of CD4+ cells was significantly lower on days 3 (38.91 +/- 2.49) and 10 (40.45 +/- 2.24) of therapy, and this decrease persisted after dexamethasone was stopped (36.73 +/- 3.41). The absolute number of CD4 cells was significantly lower on day 10 (1328 +/- 216) of therapy and reached a nadir on day 56 (1143 +/- 106). Similarly, the CD4/CD8 ratio was also significantly lower on days 3 and 10 of treatment (1.56 +/- 0.18 and 1.64 +/- 0.14, respectively) and reached a nadir on day 56 (1.04 +/- 0.13). CONCLUSION: Dexamethasone significantly reduced the percentage and absolute number of lymphocytes, T cells, and CD4 cells, as well as the CD4/CD8 ratio. A reduction in CD4 cells and in the CD4/CD8 ratio persisted 2 weeks after dexamethasone therapy was stopped. In contrast, the absolute number of B cells increased transiently, and CD8 cells were unaffected by dexamethasone. This alteration in lymphocyte subpopulations may help account for the clinically beneficial anti-inflammatory effect of dexamethasone in the treatment of BPD complicated by respiratory failure. The dexamethasone-induced decrease in CD4 cells may also increase the susceptibility of these infants to infection.

Visualization of high- and low-affinity beta-adrenergic receptors in rat lung: upregulation by chronic hypoxia.

Chronic hypoxia induces a hyperadrenergic state which down-regulates beta-adrenergic receptors (beta-AR) in the heart. We visualized lung beta-AR binding sites after adaptation to chronic hypoxia by autoradiography of whole lung sections labeled with 50 pM 125I-labeled pindolol. A low concentration of agonist (32 nM isoproterenol) selectively masked beta-ARs with high affinity for agonists. Total specific beta-AR binding increased twofold with hypoxia. In both the control and hypoxic lung sections, 60-70% of the beta-ARs were in a high-affinity state, which could be reversed by guanine nucleotide. Autoradiography revealed a high density of high- and low-affinity beta-AR sites in lung parenchyma, predominantly involving alveolar walls, but also the walls of airways and blood vessels. The distribution of high- and low-affinity beta-AR within the lung was qualitatively identical. Hypoxia increased beta-AR binding without affecting its distribution. The majority of the additional beta-ARs induced during adaptation to chronic hypoxia are in the high-affinity state, and are thus of probable functional significance.