Impact of heteroresistance on treatment outcomes of people with drug-resistant TB.

BACKGROUND: Poor treatment outcomes among people with drug-resistant TB (DR-TB) are a major concern. Heteroresistance (presence of susceptible and resistant Mycobacterium tuberculosis in the same sample) has been identified in some people with TB, but its impact on treatment outcomes is unknown. METHODS: We used targeted deep sequencing to identify mutations associated with DR-TB and heteroresistance in culture samples of 624 people with DR-TB. We evaluated the association between heteroresistance and time to unfavorable treatment outcome using Cox proportional hazards regression. RESULTS: The proportion of drug-resistant isolates with a known mutation conferring resistance was lower for streptomycin (45.2%) and second-line injectables (79.1%) than for fluoroquinolones (86.7%), isoniazid (93.2%) and rifampin (96.5%). Fifty-two (8.3%) had heteroresistance, and it was more common for fluoroquinolones (4.6%) than rifampin (2.2%), second-line injectables (1.4%), streptomycin (1.7%), or isoniazid (1.3%). There was no association between heteroresistance and time to unfavorable outcome among people with multidrug-resistant TB (adjusted hazard ratio [aHR] 1.74, 95% CI 0.39-7.72) or pre-extensively DR-TB (aHR 0.65, 95% CI 0.24-1.72). CONCLUSIONS: Heteroresistance was relatively common (8.3%) among people with DR-TB in the Philippines. However, we found insufficient evidence to demonstrate an impact on unfavorable treatment outcomes.

CONTEXTE: Les résultats médiocres du traitement chez les personnes atteintes de TB résistante aux médicaments (DR-TB, pour l'anglais « drug-resistant TB ¼) constituent une préoccupation significative. L'hétérorésistance, caractérisée par la coexistence de souches sensibles et résistantes de Mycobacterium tuberculosis dans un même échantillon, a été observée chez certains patients, mais les conséquences de cette situation sur l'efficacité des traitements demeurent incertaines. MÉTHODES: Nous avons recouru au séquençage profond ciblé afin d'identifier les mutations liées à la DR-TB et à l'hétérorésistance dans les échantillons de culture provenant de 624 personnes atteintes de DR-TB. Nous avons analysé le lien entre l'hétérorésistance et le délai jusqu'à l'issue défavorable du traitement en utilisant une régression des risques proportionnels de Cox. RÉSULTATS: La proportion d'isolats, présentant une mutation connue associée à la résistance, était inférieure pour la streptomycine (45,2%) et les médicaments injectables de deuxième ligne (79,1%) par rapport aux fluoroquinolones (86,7%), à l'isoniazide (93,2%) et à la rifampicine (96,5%). Parmi les isolats, cinquante-deux (8,3%) manifestaient une hétérorésistance, plus courante pour les fluoroquinolones (4,6%) que pour la rifampicine (2,2%), les médicaments injectables de deuxième ligne (1,4%), la streptomycine (1,7%) ou l'isoniazide (1,3%). Aucune association n'a été observée entre l'hétérorésistance et un délai d'évolution défavorable chez les patients atteints de TB multirésistante (rapport de risque ajusté [aHR] 1,74 ; IC à 95% 0,39­7,72) ou de DR-TB pré-extensive (aHR 0,65 ; IC à 95% 0,24­1,72). CONCLUSIONS: L'hétérorésistance a été observée de manière relativement fréquente (8,3%) chez les personnes atteintes de DR-TB aux Philippines. Néanmoins, nous n'avons pas identifié de preuves suffisantes pour établir un lien avec des résultats de traitement défavorables.

Combined optimization of spot positions and weights for better FLASH proton therapy.

Objective.In Intensity Modulated Proton Therapy (IMPT), the weights of individual pencil-beams or spots are optimized to fulfil dosimetric constraints. Theses spots are usually located on a regular lattice and their positions are fixed during optimization. In many cases, the range of spot weights may however be limited, leading sometimes to sub-optimal plan quality. An emblematic use case is the delivery of a plan at ultra-high dose rate (FLASH-RT), for which the spot weights are typically constrained to high values.Approach. To improve further the quality of IMPT FLASH plans, we propose here a novel algorithm to optimize both the spot weights and positions directly based on the objectives defined by the treatment planner.Main results. For all cases considered, optimizing the spot positions lead to an enhanced dosimetric score, while maintaining a high dose rate.Significance. Overall, this approach resulted in a substantial plan quality improvement compared to optimizing only the spot weights, and in a similar execution time.

ClimApp-Integrating Personal Factors with Weather Forecasts for Individualised Warning and Guidance on Thermal Stress.

This paper describes the functional development of the ClimApp tool (available for free on iOS and Android devices), which combines current and 24 h weather forecasting with individual information to offer personalised guidance related to thermal exposure. Heat and cold stress assessments are based on ISO standards and thermal models where environmental settings and personal factors are integrated into the ClimApp index ranging from -4 (extremely cold) to +4 (extremely hot), while a range of -1 and +1 signifies low thermal stress. Advice for individuals or for groups is available, and the user can customise the model input according to their personal situation, including activity level, clothing, body characteristics, heat acclimatisation, indoor or outdoor situation, and geographical location. ClimApp output consists of a weather summary, a brief assessment of the thermal situation, and a thermal stress warning. Advice is provided via infographics and text depending on the user profile. ClimApp is available in 10 languages: English, Danish, Dutch, Swedish, Norwegian, Hellenic (Greek), Italian, German, Spanish and French. The tool also includes a research functionality providing a platform for worker and citizen science projects to collect individual data on physical thermal strain and the experienced thermal strain. The application may therefore improve the translation of heat and cold risk assessments and guidance for subpopulations. ClimApp provides the framework for personalising and downscaling weather reports, alerts and advice at the personal level, based on GPS location and adjustable input of individual factors.

WE-E-BRB-09: A GPU-Based Monte Carlo QA Tool for IMRT and VMAT.

PURPOSE: To develop a GPU-based Monte Carlo (MC) 3D dosimetry quality assurance (QA) tool employing patient geometry and actual delivery information. METHODS: First, we generate fluence maps at all beam angles from the initial treatment plan. A GPU-based MC dose engine, gDPM, is employed for the secondary dose calculation (SDC) on patient CT. This SDC is used to verify the TPS plan dose (PD) accuracy. Before the 1st treatment fraction, we deliver the treatment plan on a Linac without any phantom setup to obtain machine log files. With the log files, we extract actually delivered fluence maps at all beam angles and perform delivered dose calculation (DDC) using gDPM. The difference between DDC and SDC indicates possible errors in data transferring and machine delivery. Lastly, the comparison between DDC and PD shows the accumulative errors from all the possible sources. Moreover, a web application for this QA tool is developed for clinical use. We have tested this QA tool on 6 patients, 4 VMAT and 2 IMRT patients. We reported mean gamma values and passing rates inside the 20% isodose line; DVH plot and dose difference matrix are also documented. RESULTS: For all six patients, the gamma passing rates within the 20% isodose line for SDC, DDC and PD comparisons are all higher than 95%. In the DVH plot, the three dose distributions were found to be very close. A typical IMRT or VMAT case takes less than one minute to run the whole QA tool. CONCLUSIONS: We have developed a GPU-based MC QA tool which can be used for efficient and easy IMRT and VMAT QA.

SU-E-T-213: Development of a Web Wrapper to Facilitate Radiotherapy Research.

PURPOSE: Researchers write many computer programs with unique implementations, usually requiring a great amount of effort for other researchers to learn how to install, configure, and use. Some programs require specialized hardware platforms such as GPU workstation or CPU cluster, which may not readily available for many researchers. This work develops a general web platform to 'wrap' radiotherapy software tools into a user friendly, browser-based interface. METHODS: We developed a web wrapper based on existing technologies (e.g. HTML5, JavaScript, PHP, Python, XML) to interface with command line-based research tools. This wrapper enables users to easily perform various tasks in any modern web browser, while underlying tools are launched remotely. Visitors can upload data, configure settings, process data remotely, then view, share, and download results with minimal effort. This web wrapper is developer friendly; new tools are easily integrated by editing XML configuration files. RESULTS: As a test case, we have successfully wrapped a set of command line tools, developed by our group, into a single web app, providing fluence map generation, CT image processing, and GPU-based Monte Carlo (MC) dose calculation. The result is a web-based quality assurance tool. With this tool, users can upload compressed DICOM-RT files, recompute dose using the MC method, and evaluate the results by viewing dose distribution, 3D gamma index distribution and DVH curves. The entire work-flow can be completed within 2 minutes provided users have a reasonable Internet connection speed. CONCLUSIONS: We have developed an web wrapper to increase the accessibility of radiotherapy tools and reduce users' learning curve through a friendly web-based interface. This work also allows quick and easy deployment and distribution of software tools developed by researchers to the whole community.

Thermal dehydration-induced thirst in spontaneously hypertensive rats.

Spontaneously hypertensive (SH) rats and normotensive Wistar-Kyoto (WKY) rats were exposed to either 25 or 37.5 degrees C for 3.5 h, and their thermal and water balance responses were compared. After exposure, either a blood sample was obtained or the rats were allowed to rehydrate for 4 h. SH rats had both higher core temperatures and evaporative water losses during heat exposure. Measurements of hematocrit, hemoglobin concentration, plasma protein and sodium concentrations, and plasma osmolality indirectly showed that the SH rats were dehydrated relative to the WKY rats after exposure to either 25 or 37.5 degrees C. SH rats drank significantly more water but also had significantly higher urine volumes than the WKY rats and thus rehydrated only slightly better than the WKY rats. SH and WKY rats had similar levels of water intake and urine output after 24 h of water deprivation. The elevated thermal response of SH rats to heat exposure does not appear to lead to uncompensatable changes in body water status.

The effects of REM sleep deprivation on the level of sleepiness/alertness.

STUDY OBJECTIVES: The purpose of this study was to evaluate the effects of acute REM deprivation on daytime sleepiness/alertness, as measured by the MSLT. PARTICIPANTS: Twenty-six healthy, normal volunteers (14 males and 12 females) participated in this study. Participating subjects were in good physical and psychological health and were asymptomatic as to sleep/wake complaints. INTERVENTIONS: Subjects spent 5 nights and 5 days in the laboratory. The first night and day were utilized for screening purposes. The remaining stay in the laboratory consisted of a baseline night and day, 2 deprivation nights and days, and a recovery night and day. Each night, a nocturnal polysomnogram was employed to monitor subjects' sleep. Each day, subjects underwent an MSLT to evaluate their sleepiness/alertness. Subjects were randomized into REM-deprivation (RD) and yoked-control (YC) groups. On deprivation nights, RD subjects were awakened each time they entered stage REM sleep, and the YC subjects were awakened concomitantly with the RD subjects, assuming they were not in stage REM sleep. RESULTS: The REM-deprived subjects did not demonstrate any changes in MSLT scores across experimental days. In contrast, the YC subjects documented significantly lower MSLT scores on deprivation days due to decreased total sleep time. CONCLUSION: The REM-deprivation procedure antagonized the effects of sleep loss on daytime sleepiness, resulting in increased alertness for RD subjects compared to YC subjects. The mechanism by which REM deprivation exerts its alerting effects is unknown and will require future research.

The perception of sleep as a function of the level of daytime sleepiness among patients with obstructive sleep apnea.

Subjective estimates of sleep onset among patients with a variety of sleep disorders have been shown to be inaccurate. This inability in perceiving sleep onset is potentially dangerous for this population, in particular, for individuals who are required to drive long distances or operate heavy machinery as part of their daily activities. This study evaluated the perception of sleep among 237 consecutive patients diagnosed with obstructive sleep apnea. Patients completed an overnight sleep-laboratory evaluation followed by an objective evaluation of sleep propensity. The latter was done using the Multiple Sleep Latency Test (MSLT). Patients with an accurate perception of having slept on the MSLT were found to have shorter sleep latencies when compared with those with an inaccurate perception of their sleep. The results of this study suggest that the rapidity with which sleep is manifested is an important contributor to the accurate perception of sleep.

Disruption of MAP-2 immunostaining in rat hippocampus after traumatic brain injury.

The effects of diffuse brain injury on dendritic morphology in rat hippocampus and cortex were examined in this study using the recently described impact acceleration model of traumatic brain injury (Marmarou et al., 1994). Dendritic structure was visualized using immunostaining of microtubule associated protein-2 (MAP-2). Brains were studied 24, 48, and 72 h after brain injury. Results from immunohistochemistry and light microscopy indicated a time-dependent disruption of dendritic cytoarchitecture in the CA1 subregion and in the hilus of the hippocampus but not in the dentate gyrus or CA3 subregion. Similar disruption was observed in the cortical mantle overlying the hippocampus. Although disruption of dendritic structure was observed at 24 h, the most severe damage was at 48 h after injury with evidence of at least partial recovery of MAP-2 immunostaining by 72 h. In the most severe damage, dendrites appeared to be fragmented, scattered, and unaligned, consisting of irregularly spaced and darkly stained swollen segments. A mixed pattern of immunostaining was observed in somata of hilar cells, with some appearing normal while others stained only faintly, appearing to have lost their typical polygonal shape. Semiquantitative rankings confirmed these qualitative findings. Immediate post-injury behavioral evaluations of injury severity were compared to the degree of disruption of MAP-2 immunostaining. The results of this study indicate that diffuse brain injury is associated not only with axonal damage but also with injury to dendrites.

The reliability of the diagnostic features in patients with narcolepsy.

This study determined the test-retest reliability of the polysomnographic findings in narcolepsy. The diagnosis of narcolepsy was based on clinical symptoms and polysomnographic signs. Control subjects were screened before participation and were split based on their screening multiple sleep latency test (MSLT) into high- and low-MSLT groups. Subjects completed two polysomnographic evaluations with at least 5 days between laboratory tests. Narcoleptics had lower sleep efficiencies and high stage 1% when compared to the low MSLT control group. They had more awakenings and less stage 2% than the control groups. Narcoleptics had a shorter latency to 1 when compared to the high-MSLT group but comparable to that of the low-MSLT group. Narcoleptics had a higher number of sleep-onset rapid eye movement periods (SOREMPs) than both control groups. The MSLT scores were stable across the two evaluations and showed a statistically significant correlation. Twenty-eight of the 30 narcoleptic subjects had two or more SOREMPs on reevaluation. None of the controls had multiple SOREMPs. Thus, multiple SOREMPs were shown to be a reliable finding in patients with narcolepsy.

Thermal dehydration-induced thirst in rats: role of body temperature.

Male Sprague-Dawley rats were used to study the possible role of hyperthermia in the thirst associated with thermal dehydration. Rats were exposed to 40 degrees C for 4 h and then allowed access to water at different times after they were transferred to 25 degrees C. Delaying the time prior to allowing the rats to drink did not significantly alter either water intake or percent rehydration even though core temperature decreased during the first 1.5 h after removal from the heat. Exposing thermally dehydrated rats to 5 degrees C for 30 min prior to allowing them access to water also failed to significantly affect water intake or percent rehydration. Thermally dehydrated rats allowed to drink while remaining in the heat did not show a significant increase in water intake during the first hour or percent rehydration over rats drinking at 25 degrees C. Nondehydrated rats did show significant increases in water intake and percent rehydration when allowed to drink in the heat. Hyperthermia does not play a role in drinking in thermally dehydrated rats but can stimulate drinking in water-replete rats.