Reaction Pathways for the Enzymatic Degradation of Poly(Ethylene Terephthalate): What Characterizes an Efficient PET-Hydrolase?

Bioprocessing of polyester waste has emerged as a promising tool in the quest for a cyclic plastic economy. One key step is the enzymatic breakdown of the polymer, and this entails a complicated pathway with substrates, intermediates, and products of variable size and solubility. We have elucidated this pathway for poly(ethylene terephthalate) (PET) and four enzymes. Specifically, we combined different kinetic measurements and a novel stochastic model and found that the ability to hydrolyze internal bonds in the polymer (endo-lytic activity) was a key parameter for overall enzyme performance. Endo-lytic activity promoted the release of soluble PET fragments with two or three aromatic rings, which, in turn, were broken down with remarkable efficiency (kcat /KM values of about 105  M-1 s-1 ) in the aqueous bulk. This meant that approximatly 70 % of the final, monoaromatic products were formed via soluble di- or tri-aromatic intermediates.

Dose planning study of proton versus photon radiotherapy for head and neck squamous cell carcinoma of unknown primary in the primary and recurrent setting.

BACKGROUND: Patients with head and neck squamous cell carcinoma of unknown primary (HNCUP) are often treated with extensive radiotherapy (RT). Frequently, the bilateral nodal clinical target volume (nCTV) and the volumes of suspected mucosal primary sites (mCTV) of the pharynx and larynx is irradiated. This treatment is effective but toxic. New data suggest that omission of the contralateral nCTV and mCTV, results in few recurrences. The present study explores photon versus proton therapy, in the primary and recurrent setting. MATERIAL AND METHODS: An analysis of twelve patients previously treated for HNCUP was performed. A fictitious recurrence was defined in patients treated for unilateral disease. Independently a volumetric arc photon plan and an intensity-modulated proton plan was made for all cases and scenarios. RESULTS: Compared to the standard bilateral treatment this study shows that limiting the target to unilateral nCTV leads to a significant decrease in dysphagia of 18% and 17% and xerostomia of 4.0% and 5% for photon and protons, respectively. Comparing photon RT directly to proton RT shows a small and often insignificant gain, using protons for both bilateral and unilateral targets. Focusing on re-irradiation, benefits from using protons in both the primary setting and at re-irradiation were limited. However, using protons for re-irradiation only leads to a decrease in the tissue volume receiving a specific dose outside the target overlapping region, e.g., V90Gymean was 31, 25, and 22 cm3 for photons-photons, photons-protons, and protons-protons, respectively. For V100Gy of the ipsilateral carotid artery, no differences were observed. CONCLUSION: Omitting contralateral nCTV irradiation and mCTV irradiation will significantly reduce toxicity. The accumulated high dose volumes can be minimised using protons for re-irradiation. However, the use of protons for primary treatment provides limited benefit in most patients.

Consistency in contouring of organs at risk by artificial intelligence vs oncologists in head and neck cancer patients.

BACKGROUND: In the Danish Head and Neck Cancer Group (DAHANCA) 35 trial, patients are selected for proton treatment based on simulated reductions of Normal Tissue Complication Probability (NTCP) for proton compared to photon treatment at the referring departments. After inclusion in the trial, immobilization, scanning, contouring and planning are repeated at the national proton centre. The new contours could result in reduced expected NTCP gain of the proton plan, resulting in a loss of validity in the selection process. The present study evaluates if contour consistency can be improved by having access to AI (Artificial Intelligence) based contours. MATERIALS AND METHODS: The 63 patients in the DAHANCA 35 pilot trial had a CT from the local DAHANCA centre and one from the proton centre. A nationally validated convolutional neural network, based on nnU-Net, was used to contour OARs on both scans for each patient. Using deformable image registration, local AI and oncologist contours were transferred to the proton centre scans for comparison. Consistency was calculated with the Dice Similarity Coefficient (DSC) and Mean Surface Distance (MSD), comparing contours from AI to AI and oncologist to oncologist, respectively. Two NTCP models were applied to calculate NTCP for xerostomia and dysphagia. RESULTS: The AI contours showed significantly better consistency than the contours by oncologists. The median and interquartile range of DSC was 0.85 [0.78 - 0.90] and 0.68 [0.51 - 0.80] for AI and oncologist contours, respectively. The median and interquartile range of MSD was 0.9 mm [0.7 - 1.1] mm and 1.9 mm [1.5 - 2.6] mm for AI and oncologist contours, respectively. There was no significant difference in ΔNTCP. CONCLUSIONS: The study showed that OAR contours made by the AI algorithm were more consistent than those made by oncologists. No significant impact on the ΔNTCP calculations could be discerned.

Interaural Place-of-Stimulation Mismatch Estimates Using CT Scans and Binaural Perception, But Not Pitch, Are Consistent in Cochlear-Implant Users.

Bilateral cochlear implants (BI-CIs) or a CI for single-sided deafness (SSD-CI; one normally functioning acoustic ear) can partially restore spatial-hearing abilities, including sound localization and speech understanding in noise. For these populations, however, interaural place-of-stimulation mismatch can occur and thus diminish binaural sensitivity that relies on interaurally frequency-matched neurons. This study examined whether plasticity-reorganization of central neural pathways over time-can compensate for peripheral interaural place mismatch. We hypothesized differential plasticity across two systems: none for binaural processing but adaptation for pitch perception toward frequencies delivered by the specific electrodes. Interaural place mismatch was evaluated in 19 BI-CI and 23 SSD-CI human subjects (both sexes) using binaural processing (interaural-time-difference discrimination with simultaneous bilateral stimulation), pitch perception (pitch ranking for single electrodes or acoustic tones with sequential bilateral stimulation), and physical electrode-location estimates from computed-tomography (CT) scans. On average, CT scans revealed relatively little BI-CI interaural place mismatch (26° insertion-angle mismatch) but a relatively large SSD-CI mismatch, particularly at low frequencies (166° for an electrode tuned to 300 Hz, decreasing to 14° at 7000 Hz). For BI-CI subjects, the three metrics were in agreement because there was little mismatch. For SSD-CI subjects, binaural and CT measurements were in agreement, suggesting little binaural-system plasticity induced by mismatch. The pitch measurements disagreed with binaural and CT measurements, suggesting place-pitch plasticity or a procedural bias. These results suggest that reducing interaural place mismatch and potentially improving binaural processing by reprogramming the CI frequency allocation would be better done using CT-scan than pitch information.SIGNIFICANCE STATEMENT Electrode-array placement for cochlear implants (bionic prostheses that partially restore hearing) does not explicitly align neural representations of frequency information. The resulting interaural place-of-stimulation mismatch can diminish spatial-hearing abilities. In this study, adults with two cochlear implants showed reasonable interaural alignment, whereas those with one cochlear implant but normal hearing in the other ear often showed mismatch. In cases of mismatch, binaural sensitivity was best when the same cochlear locations were stimulated in both ears, suggesting that binaural brainstem pathways do not experience plasticity to compensate for mismatch. In contrast, interaurally pitch-matched electrodes deviated from cochlear-location estimates and did not optimize binaural sensitivity. Clinical correction of interaural place mismatch using binaural or computed-tomography (but not pitch) information may improve spatial-hearing benefits.

Analysis of fungal high-mannose structures using CAZymes.

Glycoengineering ultimately allows control over glycosylation patterns to generate new glycoprotein variants with desired properties. A common challenge is glycan heterogeneity, which may affect protein function and limit the use of key techniques such as mass spectrometry. Moreover, heterologous protein expression can introduce nonnative glycan chains that may not fulfill the requirement for therapeutic proteins. One strategy to address these challenges is partial trimming or complete removal of glycan chains, which can be obtained through selective application of exoglycosidases. Here, we demonstrate an enzymatic O-deglycosylation toolbox of a GH92 α-1,2-mannosidase from Neobacillus novalis, a GH2 ß-galactofuranosidase from Amesia atrobrunnea and the jack bean α-mannosidase. The extent of enzymatic O-deglycosylation was mapped against a full glycosyl linkage analysis of the O-glycosylated linker of cellobiohydrolase I from Trichoderma reesei (TrCel7A). Furthermore, the influence of deglycosylation on TrCel7A functionality was evaluated by kinetic characterization of native and O-deglycosylated forms of TrCel7A. This study expands structural knowledge on fungal O-glycosylation and presents a ready-to-use enzymatic approach for controlled O-glycan engineering in glycoproteins expressed in filamentous fungi.

A Longitudinal Study of Ebola Sequelae in Liberia.

BACKGROUND: Multiple health problems have been reported in survivors of Ebola virus disease (EVD). Attribution of these problems to the disease without a control group for analysis is difficult. METHODS: We enrolled a cohort of EVD survivors and their close contacts and prospectively collected data on symptoms, physical examination findings, and laboratory results. A subset of participants underwent ophthalmologic examinations. Persistence of Ebola virus (EBOV) RNA in semen samples from survivors was determined. RESULTS: A total of 966 EBOV antibody-positive survivors and 2350 antibody-negative close contacts (controls) were enrolled, and 90% of these participants were followed for 12 months. At enrollment (median time to baseline visit, 358 days after symptom onset), six symptoms were reported significantly more often among survivors than among controls: urinary frequency (14.7% vs. 3.4%), headache (47.6% vs. 35.6%), fatigue (18.4% vs. 6.3%), muscle pain (23.1% vs. 10.1%), memory loss (29.2% vs. 4.8%), and joint pain (47.5% vs. 17.5%). On examination, more survivors than controls had abnormal abdominal, chest, neurologic, and musculoskeletal findings and uveitis. Other than uveitis (prevalence at enrollment, 26.4% vs. 12.1%; at year 1, 33.3% vs. 15.4%), the prevalence of these conditions declined during follow-up in both groups. The incidence of most symptoms, neurologic findings, and uveitis was greater among survivors than among controls. EBOV RNA was detected in semen samples from 30% of the survivors tested, with a maximum time from illness to detection of 40 months. CONCLUSIONS: A relatively high burden of symptoms was seen in all participants, but certain symptoms and examination findings were more common among survivors. With the exception of uveitis, these conditions declined in prevalence during follow-up in both groups. Viral RNA in semen persisted for a maximum of 40 months. (Funded by the National Institute of Allergy and Infectious Diseases and the National Eye Institute; PREVAIL III ClinicalTrials.gov number, NCT02431923.).

Target coverage and local recurrences after radiotherapy for sinonasal cancer in Denmark 2008-2015. A DAHANCA study.

PURPOSE: The study aimed to investigate the pattern of failure and describe compromises in the definition and coverage of the target for patients treated with curatively intended radiotherapy (RT) for sinonasal cancer (SNC). METHODS AND MATERIAL: Patients treated with curatively intended RT in 2008-2015 in Denmark for SNC were eligible for the retrospective cohort study. Information regarding diagnosis and treatment was retrieved from the national database of the Danish Head and Neck Cancer Group (DAHANCA). Imaging from the diagnosis of recurrences was collected, and the point of origin (PO) of the recurrent tumour was estimated. All treatment plans were collected and reviewed with the focus on target coverage, manual modifications of target volumes, and dose to organs at risk (OARs) above defined constraints. RESULTS: A total of 184 patients were included in the analysis, and 76 (41%) relapsed. The majority of recurrences involved T-site (76%). Recurrence imaging of 39 patients was evaluated, and PO was established. Twenty-nine POs (74%) were located within the CTV, and the minimum dose to the PO was median 64.1 Gy (3.1-70.7). The criteria for target coverage (V95%) was not met in 89/184 (48%) of the CTV and 131/184 (71%) of the PTV. A total of 24% of CTVs had been manually modified to spare OARs of high-dose irradiation. No difference in target volume modifications was observed between patients who suffered recurrence and patients with lasting remission. CONCLUSION: The majority of relapses after radical treatment of SNC were located in the T-site (the primary tumour site). Multiple compromises with regards to target coverage and tolerance levels for OARs in the sinonasal region, as defined from RT guidelines, were taken. No common practice in this respect could be derived from the study.

International assessment of interobserver reproducibility of flap delineation in head and neck carcinoma.

Background: Several reports have suggested that radiotherapy after reconstructive surgery for head and neck cancer (HNC), could have deleterious effects on the flaps with respect to functional outcomes. To predict and prevent toxicities, flap delineation should be accurate and reproducible. The objective of the present study was to evaluate the interobserver variability of frequent types of flaps used in HNC, based on the recent GORTEC atlas.Materials and methods: Each member of an international working group (WG) consisting of 14 experts delineated the flaps on a CT set from six patients. Each patient had one of the five most commonly used flaps in HNC: a regional pedicled pectoralis major myocutaneous flap, a local pedicled rotational soft tissue facial artery musculo-mucosal (FAMM) (2 patients), a fasciocutaneous radial forearm free flap, a soft tissue anterolateral thigh (ALT) free flap, or a fibular free flap. The WG's contours were compared to a reference contour, validated by a surgeon and a radiologist specializing in HNC. Contours were considered as reproducible if the median Dice Similarity Coefficient (DSC) was > 0.7.Results: The median volumes of the six flaps delineated by the WG were close to the reference contour value, with approximately 50 cc for the pectoral, fibula, and ALT flaps, 20 cc for the radial forearm, and up to 10 cc for the FAMM. The volumetric ratio was thus close to the optimal value of 100% for all flaps. The median DSC obtained by the WG compared to the reference for the pectoralis flap, the FAMM, the radial forearm flap, ALT flap, and the fibular flap were 0.82, 0.40, 0.76, 0.81, and 0.76, respectively.Conclusions: This study showed that the delineation of four main flaps used for HNC was reproducible. The delineation of the FAMM, however, requires close cooperation between radiologist, surgeon and radiation oncologist because of the poor visibility of this flap on CT and its small size.

Biopsy-based optimization and calibration of a signal-intensity-ratio-based MRI method (1.5 Tesla) in a dextran-iron loaded mini-pig model, enabling estimation of very high liver iron concentrations.

OBJECTIVE: Magnetic resonance imaging (MRI)-based techniques for non-invasive assessing liver iron concentration (LIC) in patients with iron overload have a limited upper measuring range around 35 mg/g dry weight, caused by signal loss from accelerated T1-, T2-, T2* shortening with increasing LIC. Expansion of this range is necessary to allow evaluation of patients with very high LIC. AIM: To assess measuring range of a gradient-echo R2* method and a T1-weighted spin-echo (SE), signal intensity ratio (SIR)-based method (TE = 25 ms, TR = 560 ms), and to extend the upper measuring range of the SIR method by optimizing echo time (TE) and repetition time (TR) in iron-loaded minipigs. METHODS: Thirteen mini pigs were followed up during dextran-iron loading with repeated percutaneous liver biopsies for chemical LIC measurement and MRIs for parallel non-invasive estimation of LIC (81 examinations) using different TEs and TRs. RESULTS: SIR and R2* method had similar upper measuring range around 34 mg/g and similar method agreement. Using TE = 12 ms and TR = 1200 ms extended the upper measuring range to 115 mg/g and yielded good method of agreement. DISCUSSION: The wider measuring range is likely caused by lesser sensitivity of the SE sequence to iron, due to shorter TE, leading to later signal loss at high LIC, allowing evaluation of most severe hepatic iron overload. Validation in iron-loaded patients is necessary.

Measuring Knee Joint Laxity in Three Degrees-of-Freedom In Vivo Using a Robotics- and Image-Based Technology.

Accurate and reliable information about three-dimensional (3D) knee joint laxity can prevent misdiagnosis and avoid incorrect treatments. Nevertheless, knee laxity assessments presented in the literature suffer from significant drawbacks such as soft tissue artifacts, restricting the knee within the measurement, and the absence of quantitative knee ligament property information. In this study, we demonstrated the applicability of a novel methodology for measuring 3D knee laxity, combining robotics- and image-based technology. As such technology has never been applied to healthy living subjects, the aims of this study were to develop novel technology to measure 3D knee laxity in vivo and to provide proof-of-concept 3D knee laxity measurements. To measure tibiofemoral movements, four healthy subjects were placed on a custom-built arthrometer located inside a low dose biplanar X-ray system with an approximately 60 deg knee flexion angle. Anteroposterior and mediolateral translation as well as internal and external rotation loads were subsequently applied to the unconstrained leg, which was placed inside a pneumatic cast boot. Bone contours were segmented in the obtained X-rays, to which subject-specific bone geometries from magnetic resonance imaging (MRI) scans were registered. Afterward, tibiofemoral poses were computed. Measurements of primary and secondary laxity revealed considerable interpersonal differences. The method differs from those available by the ability to accurately track secondary laxity of the unrestricted knee and to apply coupled forces in multiple planes. Our methodology can provide reliable information for academic knee ligament research as well as for clinical diagnostics in the future.

Comparative Biochemistry of Four Polyester (PET) Hydrolases*.

The potential of bioprocessing in a circular plastic economy has strongly stimulated research into the enzymatic degradation of different synthetic polymers. Particular interest has been devoted to the commonly used polyester, poly(ethylene terephthalate) (PET), and a number of PET hydrolases have been described. However, a kinetic framework for comparisons of PET hydrolases (or other plastic-degrading enzymes) acting on the insoluble substrate has not been established. Herein, we propose such a framework, which we have tested against kinetic measurements for four PET hydrolases. The analysis provided values of kcat and KM , as well as an apparent specificity constant in the conventional units of M-1 s-1 . These parameters, together with experimental values for the number of enzyme attack sites on the PET surface, enabled comparative analyses. A variant of the PET hydrolase from Ideonella sakaiensis was the most efficient enzyme at ambient conditions; it relied on a high kcat rather than a low KM . Moreover, both soluble and insoluble PET fragments were consistently hydrolyzed much faster than intact PET. This suggests that interactions between polymer strands slow down PET degradation, whereas the chemical steps of catalysis and the low accessibility associated with solid substrate were less important for the overall rate. Finally, the investigated enzymes showed a remarkable substrate affinity, and reached half the saturation rate on PET when the concentration of attack sites in the suspension was only about 50 nM. We propose that this is linked to nonspecific adsorption, which promotes the nearness of enzyme and attack sites.

Surface display as a functional screening platform for detecting enzymes active on PET.

Poly(ethylene terephthalate) (PET) is the world's most abundant polyester plastic, and its ongoing accumulation in nature is causing a global environmental problem. Currently, the main recycling processes utilize thermomechanical or chemical means, resulting in the deterioration of the mechanical properties of PET. Consequently, polluting de novo synthesis remains preferred, creating the need for more efficient and bio-sustainable ways to hydrolyze the polymer. Recently, a PETase enzyme from the bacterium Ideonella sakaiensis was shown to facilitate PET biodegradation, albeit at slow rate. Engineering of more efficient PETases is required for industrial relevance, but progress is currently hampered by the dependency on intracellular expression in Escherichia coli. To create a more efficient screening platform in E. coli, we explore different surface display anchors for fast and easy assaying of PETase activity. We show that PETases can be functionally displayed on the bacterial cell surface, enabling screening of enzyme activity on PET microparticles - both while anchored to the cell and following solubilization of the enzymes.

Goal-directed fluid therapy in emergency abdominal surgery: a randomised multicentre trial.

BACKGROUND: More than 50% of patients have a major complication after emergency gastrointestinal surgery. Intravenous (i.v.) fluid therapy is a life-saving part of treatment, but evidence to guide what i.v. fluid strategy results in the best outcome is lacking. We hypothesised that goal-directed fluid therapy during surgery (GDT group) reduces the risk of major complications or death in patients undergoing major emergency gastrointestinal surgery compared with standard i.v. fluid therapy (STD group). METHODS: In a randomised, assessor-blinded, two-arm, multicentre trial, we included 312 adult patients with gastrointestinal obstruction or perforation. Patients in the GDT group received i.v. fluid to near-maximal stroke volume. Patients in the STD group received i.v. fluid following best clinical practice. Postoperative target was 0-2 L fluid balance. The primary outcome was a composite of major complications or death within 90 days. Secondary outcomes were time in intensive care, time on ventilator, time in dialysis, hospital stay, and minor complications. RESULTS: In a modified intention-to-treat analysis, we found no difference in the primary outcome between groups: 45 (30%) (GDT group) vs 39 (25%) (STD group) (odds ratio=1.24; 95% confidence interval, 0.75-2.05; P=0.40). Hospital stay was longer in the GDT group: median (inter-quartile range), 7 (4-12) vs 6 days (4-8.5) (P=0.04); no other differences were found. CONCLUSION: Compared with pressure-guided i.v. fluid therapy (STD group), flow-guided fluid therapy to near-maximal stroke volume (GDT group) did not improve the outcome after surgery for bowel obstruction or gastrointestinal perforation but may have prolonged hospital stay. CLINICAL TRIAL REGISTRATION: EudraCT number 2015-000563-14; the Danish Scientific Ethics Committee and the Danish Data Protection Agency (REG-18-2015).

Systematic deletions in the cellobiohydrolase (CBH) Cel7A from the fungus Trichoderma reesei reveal flexible loops critical for CBH activity.

Glycoside hydrolase family 7 (GH7) cellulases are some of the most efficient degraders of cellulose, making them particularly relevant for industries seeking to produce renewable fuels from lignocellulosic biomass. The secretome of the cellulolytic model fungus Trichoderma reesei contains two GH7s, termed TrCel7A and TrCel7B. Despite having high structural and sequence similarities, the two enzymes are functionally quite different. TrCel7A is an exolytic, processive cellobiohydrolase (CBH), with high activity on crystalline cellulose, whereas TrCel7B is an endoglucanase (EG) with a preference for more amorphous cellulose. At the structural level, these functional differences are usually ascribed to the flexible loops that cover the substrate-binding areas. TrCel7A has an extensive tunnel created by eight peripheral loops, and the absence of four of these loops in TrCel7B makes its catalytic domain a more open cleft. To investigate the structure-function relationships of these loops, here we produced and kinetically characterized several variants in which four loops unique to TrCel7A were individually deleted to resemble the arrangement in the TrCel7B structure. Analysis of a range of kinetic parameters consistently indicated that the B2 loop, covering the substrate-binding subsites -3 and -4 in TrCel7A, was a key determinant for the difference in CBH- or EG-like behavior between TrCel7A and TrCel7B. Conversely, the B3 and B4 loops, located closer to the catalytic site in TrCel7A, were less important for these activities. We surmise that these results could be useful both in further mechanistic investigations and for guiding engineering efforts of this industrially important enzyme family.

Acoustic Hearing Can Interfere With Single-Sided Deafness Cochlear-Implant Speech Perception.

OBJECTIVES: Cochlear implants (CIs) restore some spatial advantages for speech understanding in noise to individuals with single-sided deafness (SSD). In addition to a head-shadow advantage when the CI ear has a better signal-to-noise ratio, a CI can also provide a binaural advantage in certain situations, facilitating the perceptual separation of spatially separated concurrent voices. While some bilateral-CI listeners show a similar binaural advantage, bilateral-CI listeners with relatively large asymmetries in monaural speech understanding can instead experience contralateral speech interference. Based on the interference previously observed for asymmetric bilateral-CI listeners, this study tested the hypothesis that in a multiple-talker situation, the acoustic ear would interfere with rather than improve CI speech understanding for SSD-CI listeners. DESIGN: Experiment 1 measured CI-ear speech understanding in the presence of competing speech or noise for 13 SSD-CI listeners. Target speech from the closed-set coordinate response-measure corpus was presented to the CI ear along with one same-gender competing talker or stationary noise at target-to-masker ratios between -8 and 20 dB. The acoustic ear was presented with silence (monaural condition) or with a copy of the competing speech or noise (bilateral condition). Experiment 2 tested a subset of 6 listeners in the reverse configuration for which SSD-CI listeners have previously shown a binaural benefit (target and competing speech presented to the acoustic ear; silence or competing speech presented to the CI ear). Experiment 3 examined the possible influence of a methodological difference between experiments 1 and 2: whether the competing talker spoke keywords that were inside or outside the response set. For each experiment, the data were analyzed using repeated-measures logistic regression. For experiment 1, a correlation analysis compared the difference between bilateral and monaural speech-understanding scores to several listener-specific factors: speech understanding in the CI ear, preimplantation duration of deafness, duration of CI experience, ear of deafness (left/right), acoustic-ear audiometric thresholds, and listener age. RESULTS: In experiment 1, presenting a copy of the competing speech to the acoustic ear reduced CI speech-understanding scores for target-to-masker ratios ≥4 dB. This interference effect was limited to competing-speech conditions and was not observed for a noise masker. There was dramatic intersubject variability in the magnitude of the interference (range: 1 to 43 rationalized arcsine units), which was found to be significantly correlated with listener age. The interference effect contrasted sharply with the reverse configuration (experiment 2), whereby presenting a copy of the competing speech to the contralateral CI ear significantly improved performance relative to monaural acoustic-ear performance. Keyword condition (experiment 3) did not influence the observed pattern of interference. CONCLUSIONS: Most SSD-CI listeners experienced interference when they attended to the CI ear and competing speech was added to the acoustic ear, although there was a large amount of intersubject variability in the magnitude of the effect, with older listeners particularly susceptible to interference. While further research is needed to investigate these effects under free-field listening conditions, these results suggest that for certain spatial configurations in a multiple-talker situation, contralateral speech interference could reduce the benefit that an SSD-CI otherwise provides.

Development and Evaluation of a Subject-Specific Lower Limb Model With an Eleven-Degrees-of-Freedom Natural Knee Model Using Magnetic Resonance and Biplanar X-Ray Imaging During a Quasi-Static Lunge.

Musculoskeletal (MS) models can be used to study the muscle, ligament, and joint mechanics of natural knees. However, models that both capture subject-specific geometry and contain a detailed joint model do not currently exist. This study aims to first develop magnetic resonance image (MRI)-based subject-specific models with a detailed natural knee joint capable of simultaneously estimating in vivo ligament, muscle, tibiofemoral (TF), and patellofemoral (PF) joint contact forces and secondary joint kinematics. Then, to evaluate the models, the predicted secondary joint kinematics were compared to in vivo joint kinematics extracted from biplanar X-ray images (acquired using slot scanning technology) during a quasi-static lunge. To construct the models, bone, ligament, and cartilage structures were segmented from MRI scans of four subjects. The models were then used to simulate lunges based on motion capture and force place data. Accurate estimates of TF secondary joint kinematics and PF translations were found: translations were predicted with a mean difference (MD) and standard error (SE) of 2.13 ± 0.22 mm between all trials and measures, while rotations had a MD ± SE of 8.57 ± 0.63 deg. Ligament and contact forces were also reported. The presented modeling workflow and the resulting knee joint model have potential to aid in the understanding of subject-specific biomechanics and simulating the effects of surgical treatment and/or external devices on functional knee mechanics on an individual level.

The fluctuating masker benefit for normal-hearing and hearing-impaired listeners with equal audibility at a fixed signal-to-noise ratio.

Normal-hearing (NH) listeners can extract and integrate speech fragments from momentary dips in the level of a fluctuating masker, yielding a fluctuating-masker benefit (FMB) for speech understanding relative to a stationary-noise masker. Hearing-impaired (HI) listeners generally show less FMB, suggesting a dip-listening deficit attributable to suprathreshold spectral or temporal distortion. However, reduced FMB might instead result from different test signal-to-noise ratios (SNRs), reduced absolute audibility of otherwise unmasked speech segments, or age differences. This study examined the FMB for nine age-matched NH-HI listener pairs, while simultaneously equalizing audibility, SNR, and percentage-correct performance in stationary noise. Nonsense syllables were masked by stationary noise, 4- or 32-Hz sinusoidally amplitude-modulated noise (SAMN), or an opposite-gender interfering talker. Stationary-noise performance was equalized by adjusting the response-set size. Audibility was equalized by removing stimulus components falling below the HI absolute threshold. HI listeners showed a clear 4.5-dB reduction in FMB for 32-Hz SAMN, a similar FMB to NH listeners for 4-Hz SAMN, and a non-significant trend toward a 2-dB reduction in FMB for an interfering talker. These results suggest that HI listeners do not exhibit a general dip-listening deficit for all fluctuating maskers, but rather a specific temporal-resolution deficit affecting performance for high-rate modulated maskers.

Cone-beam computed tomography (CBCT) for adaptive image guided head and neck radiation therapy.

BACKGROUND: Adaptive (ART) and image guided radiation therapy (IGRT) can improve target coverage and reduce unnecessary irradiation of organs at risk (OAR). The purpose of this study is to report the results of using mid-course imaging and a novel workflow with cone-beam computed tomography (CBCT) surveillance of dose to OAR to trigger adaptive replanning in head and neck radiotherapy. MATERIAL AND METHODS: Impact of radiation therapist (RTT) managed match protocol and mid-course imaging was assessed in two cohorts of consecutive patients receiving RT to the head and neck region, using computed tomography (CT) and CBCT-based dose verification respectively. In the CBCT cohort, patients at high risk of xerostomia received weekly dose surveillance, while low-risk patients received a mid-course CBCT review. For weekly surveillance, predicted total doses to parotid glands, spinal cord and brainstem were calculated. If predicted mean dose to parotid glands increased by >2 Gy or constraints to brainstem or spinal cord were exceeded, replanning was performed. RESULTS: None had replanning triggered by mid-course imaging. In the CBCT cohort, weekly surveillance of 40 patients yielded minimal reduction in mean dose to parotid glands of 0.65 Gy (range0.4-1 Gy ) for three patients. Patients were surveilled averagely 4.5 times during treatment. Time consumption per CBCT/week was 22 min (range 17-38). Number of patients needed to see to achieve any dose reduction to parotid glands was 13 or the equivalent of 22 working-hours. CONCLUSION: The tested dose surveillance algorithm resulted in a minimal dose reduction ( ≤1 Gy) to parotid glands for three of 40 patients. The proposed algorithm and workflow is thus not sustainable. Mid-course dose verification did not provide added benefit and can be safely omitted in the presence of closely monitored daily IGRT. Daily image guidance and match protocol is a safe and efficient method for identifying patients requiring adaptive replanning.

Frailty status but not age predicts complications in elderly cancer patients: a follow-up study.

OBJECTIVES: The purposes were to investigate the health status of elderly cancer patients by comprehensive geriatric assessment (CGA) and to compare the complications with respect to baseline CGA and to evaluate the need for geriatric interventions in an elderly cancer patients' population. MATERIAL: Patients aged ≥70 years with lung cancer (LC), cancer of the head and neck (HNC), colorectal cancer (CRC), or upper gastro-intestinal cancer (UGIC) are referred to the Department of Oncology for cancer treatment. METHODS: CGA was performed prior to cancer treatment and addressed the following domains: Activities of daily living (ADL), instrumental ADL (IADL), comorbidity, polypharmacy, nutrition, cognition, and depression. Complications, defined as dose reduction and discontinuation of treatment due to grade 3-4 toxicity, hospital admission, shift to palliative treatment, or death within 90 days, were identified from the medical files. Patients were classified as fit, vulnerable, or frail by CGA. PRINCIPAL RESULTS: Patients (N = 217) with a median age of 75 years (range: 70-93 yeas) were included: 13% were fit, 35% vulnerable, and 52% frail. CGA significantly predicted admittance to hospital in frail and vulnerable patients compared to fit patients: risk ratio (RR) 2.12 (95% CI: 1.01; 4.46). Vulnerable and frail patients had higher absolute risk of death within 90 days compared to fit patients: 7% and 23% versus 0%. HR for death within 90 days in frail patients as compared to vulnerable patients was 3.50 (95% CI: 1.34; 9.15). More frail patients (88%) needed geriatric interventions than the vulnerable (46%) and fit patients (32%). Major conclusion: Few elderly cancer patients seem to be fit. CGA predicts admittance to hospital in a population of elderly patients with mixed cancer diseases. Frail and vulnerable patients have higher risk of death within 90 days as compared to fit patients.