Pharmacokinetic Evidence from the HIRIF Trial To Support Increased Doses of Rifampin for Tuberculosis.

Rifamycins exhibit concentration-dependent killing of Mycobacterium tuberculosis; higher exposures potentially induce better outcomes. We randomized 180 tuberculosis patients in Peru to receive rifampin at 10, 15, or 20 mg/kg/day. A total of 168 had noncompartmental pharmacokinetic analyses; 67% were sampled twice, and 33% were sampled six times. The doses administered were well tolerated. The median area under the concentration-time curve from 0 to 6 h (interquartile range) was 24.9 (17.6 to 32.1), 43.1 (30.3 to 57.5), or 55.5 (35.7 to 73.2) h · µg/ml. The median maximum drug concentration in serum in the experimental arms reached the target of 8 µg/ml. Continued investigation of higher rifampin doses is warranted. (This study has been registered at ClinicalTrials.gov under registration no. NCT01408914.).

Estimating the global burden of multidrug-resistant tuberculosis among prevalent cases of tuberculosis.

BACKGROUND: Estimates of the multidrug-resistant tuberculosis (MDR-TB) burden are based on incomplete, infrequently updated data among a limited pool of notified or incident pulmonary TB cases. METHODS: Using World Health Organization data reported by 217 countries/territories in 2014, we calculated the MDR-TB burden among prevalent TB cases and compared these with estimates among incident and notified TB patients. We also compared treatment coverage across estimates. RESULTS: Among prevalent TB patients worldwide in 2014, we estimate that 555 545 (95% credible bounds 499 340-617 391) MDR-TB cases occurred. This is 85% more than the 300 000 estimated among notified cases, and 16% more than the 480 000 among incident cases. Only 20% of MDR-TB cases among prevalent-compared to 37% of MDR-TB among notified-TB patients had access to MDR-TB treatment. Applying prior estimates, only 10% of MDR-TB cases will have successful outcomes. CONCLUSION: Estimates based on likely-to-be-diagnosed cases of MDR-TB overlook a significant proportion of morbidity, mortality, and transmission that occur in undiagnosed, untreated, prevalent TB patients. Even though it may still likely underestimate the true disease burden, MDR-TB among patients with prevalent TB represents a closer approximation of disease burden than currently reported indicators. Progress toward elimination or control depends on policies guided by a more complete representation of the disease burden.

Bayesian adaptive randomization in a clinical trial to identify new regimens for MDR-TB: the endTB trial.

BACKGROUND: Evidence-based optimization of treatment for multidrug-resistant tuberculosis (MDR-TB), including integration of new drugs, is urgent. Such optimization would benefit from efficient trial designs requiring fewer patients. Implementation of such innovative designs could accelerate improvements in and access to MDR-TB treatment. OBJECTIVE: To describe the application, advantages, and challenges of Bayesian adaptive randomization in a Phase III non-inferiority trial of MDR-TB treatment. DESIGN: endTB is the first Phase III non-inferiority trial of MDR-TB treatment to use Bayesian adaptive randomization. METHODS: We present a simulation study with assumptions for treatment response at 8, 39, and 73 weeks after randomization, on which sample size calculations are based. We show differences between Bayesian adaptive randomization and balanced randomization designs in sample size and number of patients exposed to ineffective regimens. RESULTS: With 750 participants, 27% fewer than required by balanced randomization, the study had 80% power to detect up to two (of five) novel treatment regimens that are non-inferior (margin 12%) to the control (70% estimated efficacy) at 73 weeks post randomization. Comparing Bayesian adaptive randomization to balanced randomization, up to 25% more participants would receive non-inferior regimens. CONCLUSION: Bayesian adaptive randomization may expose fewer participants to ineffective treatments and enhance the efficiency of MDR-TB treatment trials.

(Re)moving the needle: prospects for all-oral treatment for multidrug-resistant tuberculosis.

BACKGROUND: Currently recommended regimens for multidrug-resistant tuberculosis (MDR-TB) contain painful daily injections and are unsuccessful in approximately half of patients. Removal of the injectable agent to fashion all-oral regimens could transform MDR-TB treatment and access to care. OBJECTIVE: To explore evidence for all-oral treatment regimens. DESIGN: We review evidence on drugs that could be included in injection-free MDR-TB regimens. The oral drugs considered have an indication for or are recommended for off-label use for TB or MDR-TB, and have demonstrated bactericidal activity. Drugs with weak bactericidal activity should have limited prior population exposure and evidence of effectiveness in MDR-TB regimens. RESULTS: Bedaquiline, delamanid, and linezolid all display strong bactericidal activity, while clofazimine has weak bactericidal activity. They all have limited prior population exposure and demonstrated effectiveness in MDR-TB regimens. Despite widespread exposure to pyrazinamide and late-generation fluoroquinolones in the population, all are bactericidal and have shown great value when included in treatment regimens for MDR-TB. CONCLUSION: The evidence supports the use of all-oral regimens comprising new and existing drugs for MDR-TB treatment. Existing evidence of bactericidal activity and efficacy for these drugs provides a convincing argument for transitioning MDR-TB treatment towards all-oral regimens. These new regimens could mitigate the delivery, cost, and adherence challenges inherent to the current standard.

Preliminary assessment of methods used to demonstrate nut-cracking behavior to five captive chimpanzees (Pan troglodytes).

Chimpanzees acquire nut-cracking skills by observation and trial and error. Studies of captive chimpanzees have shown the effectiveness of a skilled demonstrator. We examined the effectiveness of 3 live demonstration forms from which subjects could learn nut-cracking skills: a video of proficient conspecifics, human demonstration and the presence of a skilled conspecific performing the task. A male subject did not learn to crack open nuts after viewing a video of proficient conspecifics but quickly learned the skill following a demonstration by a human facilitator. Subsequently, 4 female chimpanzees were given the opportunity to learn the skill from the now proficient male, as well as from a video and human demonstration, but failed to do so.

Down-regulation of growth factor-stimulated MAP kinase signaling in cytotoxic drug-resistant human neuroblastoma cells.

The mitogen-activated protein kinase (MAPk) signaling pathway, which plays a critical role in the proliferation of mammalian cells, is frequently up-regulated in human tumors and may contribute to the transformed phenotype. Since a major limitation of current cancer chemotherapy is prevalent resistance to cytotoxic drugs, this study determined whether alterations in growth factor signaling through MAPk may contribute to this phenomenon in human neuroblastoma cell lines. Drug-resistant SKNSH cell lines were established by long-term incubation with increasing concentrations to 10(-6) M doxorubicin (SKNSH rDOX6) or MDL 28842 (SKNSH rMDL6). The expression of epidermal growth factor receptor (EGFR) and epidermal growth factor (EGF)-induced EGFR tyrosine phosphorylation were lower in drug-resistant SKNSH cells than their wild-type counterparts. In SKNSH rDOX6 cells, decreased activation and reduced nuclear translocation of MAPk in response to EGF, or lysophosphatidic acid (LPA), or phorbol 12-myristate 13-acetate (PMA), were observed. In SKNSH rMDL6 cells, although MAPk could be activated to wild-type levels by ligand stimulation, the translocation of active MAPk to the nucleus was also reduced. These results suggest that resistance to cytotoxic drugs in human neuroblastoma cell lines is associated with a decrease in growth factor signaling through the MAPk pathway.

dissatisfaction, a gene involved in sex-specific behavior and neural development of Drosophila melanogaster.

Few mutations link well defined behaviors with individual neurons and the activity of specific genes. In Drosophila, recent evidence indicates the presence of a doublesex-independent pathway controlling sexual behavior and neuronal differentiation. We have identified a gene, dissatisfaction (dsf), that affects sex-specific courtship behaviors and neural differentiation in both sexes without an associated general behavioral debilitation. Male and female mutant animals exhibit abnormalities in courtship behaviors, suggesting a requirement for dsf in the brain. Virgin dsf females resist males during courtship and copulation and fail to lay mature eggs. dsf males actively court and attempt copulation with both mature males and females but are slow to copulate because of maladroit abdominal curling. Structural abnormalities in specific neurons indicate a role for dsf in the differentiation of sex-specific abdominal neurons. The egg-laying defect in females correlates with the absence of motor neuronal innervation on uterine muscles, and the reduced abdominal curling in males correlates with alteration in motor neuronal innervation of male ventral abdominal muscles. Epistasis experiments show that dsf acts in a tra-dependent and dsx-independent manner, placing dsf in the dsx-independent portion of the sex determination cascade.

Absent uptake on hepatobiliary scintigraphy in hepatic lobar infarction from portal vein occlusion in cholangiocarcinoma.

Hepatic infarction is an uncommon entity because of the dual blood supply to the liver. We report a case in which multimodalities demonstrate infarction of the left lobe of the liver secondary to left portal vein occlusion by an invasive cholangiocarcinoma. A 99mTc-DISIDA hepatobiliary scan showed complete absence of activity to the left of the gallbladder fossa. The differential diagnosis of absent hepatic activity on a hepatobiliary scan must include hepatic infarction.

Radiographic screening for ECT: use and usefulness.

Members of the Association for Convulsive Therapy were surveyed by mail about use of muscle relaxants and radiologic studies for ECT. One hundred eleven completed responses were received (69%), indicating that 40% routinely acquire pre-ECT spine and skull radiographs taking from 1 to 10 films. From patients receiving more than one course of ECT, 57 pre- and post-ECT pairs of films taken within 1 month of the start and end of a course, respectively, were selected. The films were identified only by age and sex of the patient and were evaluated by a radiologist. A senior psychiatrist reviewed the pre-ECT radiographic reports to determine whether a change in routine ECT procedure was required. Few clinically significant radiologic findings in the pre- or post-ECT films were noted.

Review of high-resolution CT of the lung.

High-resolution computed tomography (HRCT) of the lung provides detailed visualization of the lung parenchyma and is being used to evaluate chronic interstitial lung disease. The technique of HRCT involves use of 1-2-mm-thick collimation scans with a high spatial frequency algorithm. To fully appreciate the HRCT findings, one should understand the anatomy of the secondary pulmonary lobule. Lung disease can be classified according to pattern (linear areas, nodular areas, areas of decreased attenuation, and areas of ground-glass attenuation) and distribution (peripheral, axial, and parenchymal). Identifying the pattern and distribution of disease helps in formulating a differential diagnosis. Furthermore, when biopsy is necessary, distribution of lung disease, as seen on HRCT scans, can help in planning the approach.