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Background: This ORATOR sub-study evaluated swallowing physiology in patients treated with transoral robotic surgery (TORS) versus radiotherapy (RT) for early-stage oropharynx cancer., Methods: Swallowing physiology was evaluated using videofluoroscopy and outcomes were compared across treatment arms and correlated with MDADI scores., Results: Of the 68 patients in the ORATOR trial, 21 participated in this sub-study (30.8%), including 15 RT Arm and six TORS Arm patients. Swallowing profiles were not significantly different between the arms. MBSImP pharyngeal scores for RT Arm versus TORS Arm patients were 4.8 (±2.1) versus 4.3 (±1.5) at baseline, 6.2 (±1.2) versus 9.6 (±4.8) at 6 months and 5.9 (±1.8) versus 8.0 (±4.7) at 12 months. MBSImP pharyngeal scores demonstrated weak associations with several MDADI subscales and PAS scores., Conclusions: To best describe swallowing outcomes in studies of RT and/or surgery, instrumental swallowing assessments should be strongly considered in addition to quality of life measures., (© 2024 The Author(s). Head & Neck published by Wiley Periodicals LLC.)

Radiotherapy (RT) and transoral robotic surgery (TORS) are both curative-intent treatment options for oropharyngeal squamous cell carcinoma (OPSCC). Herein, we report the final outcomes of the ORATOR trial comparing these modalities, 5 years after enrollment completion. We randomly assigned 68 patients with T1-2N0-2 OPSCC to RT (with chemotherapy if node-positive) versus TORS plus neck dissection (± adjuvant RT/chemoradiation). The primary end point was swallowing quality of life (QOL) assessed with the MD Anderson Dysphagia Inventory (MDADI). Secondary end points included overall and progression-free survival (OS, PFS), adverse events (AEs), and other QOL metrics. The primary end point has been previously reported (Nichols 2019). In this report, the median follow-up was 5.1 years (IQR, 5.0-5.3 years). MDADI total scores converged by 5 years and were not significantly different across the follow-up period ( P = .11). EORTC QLQ-C30 and H&N35 scores demonstrated differing profiles, including worse dry mouth in the RT arm ( P = .032) and worse pain in the TORS arm ( P = .002). Grade 2-5 AE rates did not differ between arms (91% [n = 31] v 97% [n = 33] respectively, P = .61), with more neutropenia and hearing loss in the RT arm, and more dysphagia and other pain in the TORS arm based on grades 2-5 (all P < .05). There were no differences in OS or PFS. In conclusion, toxicity and QOL profiles differ in some domains between RT and TORS, but oncologic outcomes were excellent in both arms. Choice of treatment should remain a shared decision between the patient and their providers.

We describe the metagenome composition, community functional annotation, and prokaryote diversity in calcareous stromatolites from a dry stream bed of the San Felipe Creek in the Anza Borrego Desert. Analyses show a community capable of nitrogen fixation, assimilatory nitrate reduction, biofilm formation, quorum sensing, and potential thick-walled akinete formation for desiccation resistance., Competing Interests: The authors declare no conflict of interest.

Obstructive sleep apnoea-hypopnoea syndrome (OSAHS) is a common disorder characterised by repetitive episodes of the complete or partial collapse of the pharyngeal airway during sleep. This results in cessation (apnoea) or reduction (hypopnoea) of airflow, leading to oxygen desaturation and sleep fragmentation. An individual's disposition to develop OSAHS depends on the collapsibility of a segment of the upper airway. The degree of collapsibility can be quantified by the balance between occluding or extraluminal pressures of the surrounding tissues. Patients can experience snoring, unrefreshing sleep, witnessed apnoeas, waking with a choking sensation and excessive daytime sleepiness. OSAHS has a broad range of consequences, including cardiovascular, metabolic, and neurocognitive sequelae. Treatment options include lifestyle measures, in particular weight loss, and strategies to maintain upper airway patency overnight, including continuous positive airway pressure, mandibular advancement devices and positional modifiers., (© 2023 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society and the Royal Society of Biology.)

Background: Existing treatments for young people with severe depression have limited effectiveness. The aim of the Study of Ketamine for Youth Depression (SKY-D) trial is to determine whether a 4-week course of low-dose subcutaneous ketamine is an effective adjunct to treatment-as-usual in young people with major depressive disorder (MDD)., Methods: SKY-D is a double-masked, randomised controlled trial funded by the Australian Government's National Health and Medical Research Council (NHMRC). Participants aged between 16 and 25 years (inclusive) with moderate-to-severe MDD will be randomised to receive either low-dose ketamine (intervention) or midazolam (active control) via subcutaneous injection once per week for 4 weeks. The primary outcome is change in depressive symptoms on the Montgomery-Åsberg Depression Rating Scale (MADRS) after 4 weeks of treatment. Further follow-up assessment will occur at 8 and 26 weeks from treatment commencement to determine whether treatment effects are sustained and to investigate safety outcomes., Discussion: Results from this trial will be important in determining whether low-dose subcutaneous ketamine is an effective treatment for young people with moderate-to-severe MDD. This will be the largest randomised trial to investigate the effects of ketamine to treat depression in young people., Trial Registration: Australian and New Zealand Clinical Trials Registry ID: ACTRN12619000683134. Registered on May 7, 2019. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377513 ., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Conditional gene regulation in Drosophila through binary expression systems like the LexA-LexAop system provides a superb tool for investigating gene and tissue function. To increase the availability of defined LexA enhancer trap insertions, we present molecular, genetic, and tissue expression studies of 301 novel Stan-X LexA enhancer traps derived from mobilization of the index SX4 line. This includes insertions into distinct loci on the X, II, and III chromosomes that were not previously associated with enhancer traps or targeted LexA constructs, an insertion into ptc, and seventeen insertions into natural transposons. A subset of enhancer traps was expressed in CNS neurons known to produce and secrete insulin, an essential regulator of growth, development, and metabolism. Fly lines described here were generated and characterized through studies by students and teachers in an international network of genetics classes at public, independent high schools, and universities serving a diversity of students, including those underrepresented in science. Thus, a unique partnership between secondary schools and university-based programs has produced and characterized novel resources in Drosophila, establishing instructional paradigms devoted to unscripted experimental science., Competing Interests: Conflicts of interest statement The author(s) declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.)

Objective: We aimed to analyze risk factors associated with poor survival outcomes for metastatic cutaneous head-and-neck SCC to the parotid., Methods: All patients undergoing surgery for metastatic cutaneous SCC to the parotid with curative intent between 2011 and 2018, were reviewed. Demographic and clinical characteristics were evaluated. Histopathological data including tumor size and histology, tumor grade, TNM stage, resection margins, lymphovascular invasion, and perineural invasion, were analyzed. Overall survival (OS), disease-specific survival (DSS), and freedom from locoregional recurrence (LRR) were assessed., Results: Ninety patients were included (mean age, 77 years; 75 men [83.3%]). A total parotidectomy was performed in 48 patients (53.3%), and 42 (46.7%) underwent a superficial parotidectomy. Seventy patients (77.8%) underwent adjuvant RT. The median follow-up was 31 months (20-39 months). Tumor volume ≥ 50 cm 3 and a shorter RT duration (<20 days) were associated with reduced OS (p = 0.002 and p = 0.01, p = 0.02 and p = 0.009, respectively), and DSS (p = 0.004 and p = 0.02, p = 0.04 and p = 0.02, respectively) on univariable and multivariable analysis, respectively. Only a shorter RT duration was associated with worse freedom from LRR on univariable and multivariable analysis, (p = 0.04 and p < 0.001, respectively). However, with death as a competing risk, a shorter duration of RT was not significantly associated with freedom from LRR., Conclusion: A shorter duration of adjuvant RT, and excised tumor volume ≥50 cm 3 were predictive factors of reduced OS and DSS, and a shorter duration of RT was also associated with reduced freedom from LRR in patients with metastatic SCC to the parotid gland., Level of Evidence: 4 Laryngoscope, 133:1163-1168, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

We consider short-range Ising spin glasses in equilibrium at infinite system size, and prove that, for fixed bond realization and a given Gibbs state drawn from a suitable metastate, each translation and locally invariant function (for example, self-overlaps) of a single pure state in the decomposition of the Gibbs state takes the same value for all the pure states in that Gibbs state. We describe several significant applications to spin glasses.

Here, we report the discovery of a novel Sediminibacterium sequenced from laboratory cultures of freshwater stream cyanobacteria from sites in Southern California, grown in BG11 medium. Our genome-wide analyses reveal a highly contiguous and complete genome (97% BUSCO) that is placed within sediminibacterial clades in phylogenomic analyses. Functional annotation indicates the presence of genes that could be involved in mutualistic/commensal relationship with associated cyanobacterial hosts., (© The Author(s) 2022. Published by Oxford University Press on behalf of Genetics Society of America.)

Any system of coupled oscillators may be characterized by its spectrum of resonance frequencies (or eigenfrequencies), which can be tuned by varying the system's parameters. The relationship between control parameters and the eigenfrequency spectrum is central to a range of applications 1-3 . However, fundamental aspects of this relationship remain poorly understood. For example, if the controls are varied along a path that returns to its starting point (that is, around a 'loop'), the system's spectrum must return to itself. In systems that are Hermitian (that is, lossless and reciprocal), this process is trivial and each resonance frequency returns to its original value. However, in non-Hermitian systems, where the eigenfrequencies are complex, the spectrum may return to itself in a topologically non-trivial manner, a phenomenon known as spectral flow. The spectral flow is determined by how the control loop encircles degeneracies, and this relationship is well understood for [Formula: see text] (where [Formula: see text] is the number of oscillators in the system) 4,5 . Here we extend this description to arbitrary [Formula: see text]. We show that control loops generically produce braids of eigenfrequencies, and for [Formula: see text] these braids form a non-Abelian group that reflects the non-trivial geometry of the space of degeneracies. We demonstrate these features experimentally for [Formula: see text] using a cavity optomechanical system., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Importance: The optimal approach for treatment deescalation in human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCCs) is unknown., Objective: To assess a primary radiotherapy (RT) approach vs a primary transoral surgical (TOS) approach in treatment deescalation for HPV-related OPSCC., Design, Setting, and Participants: This international, multicenter, open-label parallel-group phase 2 randomized clinical trial was conducted at 9 tertiary academic cancer centers in Canada and Australia and enrolled patients with T1-T2N0-2 p16-positive OPSCC between February 13, 2018, and November 17, 2020. Patients had up to 3 years of follow-up., Interventions: Primary RT (consisting of 60 Gy of RT with concurrent weekly cisplatin in node-positive patients) vs TOS and neck dissection (ND) (with adjuvant reduced-dose RT depending on pathologic findings)., Main Outcomes and Measures: The primary end point was overall survival (OS) compared with a historical control. Secondary end points included progression-free survival (PFS), quality of life, and toxic effects., Results: Overall, 61 patients were randomized (30 [49.2%] in the RT arm and 31 [50.8%] in the TOS and ND arm; median [IQR] age, 61.9 [57.2-67.9] years; 8 women [13.6%] and 51 men [86.4%]; 31 [50.8%] never smoked). The trial began in February 2018, and accrual was halted in November 2020 because of excessive toxic effects in the TOS and ND arm. Median follow-up was 17 months (IQR, 15-20 months). For the OS end point, there were 3 death events, all in the TOS and ND arm, including the 2 treatment-related deaths (0.7 and 4.3 months after randomization, respectively) and 1 of myocardial infarction at 8.5 months. There were 4 events for the PFS end point, also all in the TOS and ND arm, which included the 3 mortality events and 1 local recurrence. Thus, the OS and PFS data remained immature. Grade 2 to 5 toxic effects occurred in 20 patients (67%) in the RT arm and 22 (71%) in the TOS and ND arm. Mean (SD) MD Anderson Dysphagia Inventory scores at 1 year were similar between arms (85.7 [15.6] and 84.7 [14.5], respectively)., Conclusions and Relevance: In this randomized clinical trial, TOS was associated with an unacceptable risk of grade 5 toxic effects, but patients in both trial arms achieved good swallowing outcomes at 1 year. Long-term follow-up is required to assess OS and PFS outcomes., Trial Registration: Clinicaltrials.gov Identifier: NCT03210103.

In classical finite-range spin systems, especially those with disorder such as spin glasses, a low-temperature Gibbs state may be a mixture of a number of pure or ordered states; the complexity of the Gibbs state has been defined in the past roughly as the logarithm of this number, assuming the question is meaningful in a finite system. As nontrivial pure-state structure is lost in finite size, in a recent paper [Phys. Rev. E 101, 042114 (2020)2470-004510.1103/PhysRevE.101.042114] Höller and the author introduced a definition of the complexity of an infinite-size Gibbs state as the mutual information between the pure state and the spin configuration in a finite region, and applied this also within a metastate construction. (A metastate is a probability distribution on Gibbs states.) They found an upper bound on the complexity for models of Ising spins in which each spin interacts with only a finite number of others, in terms of the surface area of the region, for all T≥0. In the present paper, the complexity of a metastate is defined likewise in terms of the mutual information between the Gibbs state and the spin configuration. Upper bounds are found for each of these complexities for general finite-range (i.e., short- or long-range, in a sense we define) mixed p-spin interactions of discrete or continuous spins (such as m-vector models), but only for T>0. For short-range models, the bound reduces to the surface area. For long-range interactions, the definition of a Gibbs state has to be modified, and for these models we also prove that the states obtained within the metastate constructions are Gibbs states under the modified definition. All results are valid for a large class of disorder distributions.

Purpose: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has risen rapidly, because of an epidemic of human papillomavirus infection. The optimal management of early-stage OPSCC with surgery or radiation continues to be a clinical controversy. Long-term randomized data comparing these paradigms are lacking., Methods: We randomly assigned patients with T1-T2, N0-2 (≤ 4 cm) OPSCC to radiotherapy (RT) (with chemotherapy if N1-2) versus transoral robotic surgery plus neck dissection (TORS + ND) (with or without adjuvant therapy). The primary end point was swallowing quality of life (QOL) at 1-year using the MD Anderson Dysphagia Inventory. Secondary end points included adverse events, other QOL outcomes, overall survival, and progression-free survival. All analyses were intention-to-treat. Herein, we present long-term outcomes from the trial., Results: Sixty-eight patients were randomly assigned (n = 34 per arm) between August 10, 2012, and June 9, 2017. Median follow-up was 45 months. Longitudinal MD Anderson Dysphagia Inventory analyses demonstrated statistical superiority of RT arm over time ( P = .049), although the differences beyond 1 year were of smaller magnitude than at the 1-year timepoint (year 2: 86.0 ± 13.5 in the RT arm v 84.8 ± 12.5 in the TORS + ND arm, P = .74; year 3: 88.9 ± 11.3 v 83.3 ± 13.9, P = .12). These differences did not meet the threshold to qualify as a clinically meaningful change at any timepoint. Certain differences in QOL concerns including more pain and dental concerns in the TORS + ND arm seen at 1 year resolved at 2 and 3 years; however, TORS patients started to use more nutritional supplements at 3 years ( P = .015). Dry mouth scores were higher in RT patients over time ( P = .041)., Conclusion: On longitudinal analysis, the swallowing QOL difference between primary RT and TORS + ND approaches persists but decreases over time. Patients with OPSCC should be informed about the pros and cons of both treatment options (ClinicalTrials.gov identifier: NCT01590355)., Competing Interests: Anthony C. NicholsResearch Funding: Novartis Canada Pharmaceuticals Inc (Inst) Eric BertheletResearch Funding: Eisai Eric WinquistConsulting or Advisory Role: Merck, Bayer, Eisai, Amgen, Roche, IpsenResearch Funding: Roche/Genentech (Inst), Merck (Inst), Pfizer (Inst), Eisai (Inst), Ayala Pharmaceuticals (Inst) David A. PalmaThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Employment: London Health Sciences Centre (LHSC)Patents, Royalties, Other Intellectual Property: US patent: a method for analyzing a three-dimensional computed tomography image, US patent application no. 61/896349 (not licensed, no commercial or financial impact)No other potential conflicts of interest were reported.

Genome segregation is a vital process in all organisms. Chromosome partitioning remains obscure in Archaea, the third domain of life. Here, we investigated the SegAB system from Sulfolobus solfataricus. SegA is a ParA Walker-type ATPase and SegB is a site-specific DNA-binding protein. We determined the structures of both proteins and those of SegA-DNA and SegB-DNA complexes. The SegA structure revealed an atypical, novel non-sandwich dimer that binds DNA either in the presence or in the absence of ATP. The SegB structure disclosed a ribbon-helix-helix motif through which the protein binds DNA site specifically. The association of multiple interacting SegB dimers with the DNA results in a higher order chromatin-like structure. The unstructured SegB N-terminus plays an essential catalytic role in stimulating SegA ATPase activity and an architectural regulatory role in segrosome (SegA-SegB-DNA) formation. Electron microscopy results also provide a compact ring-like segrosome structure related to chromosome organization. These findings contribute a novel mechanistic perspective on archaeal chromosome segregation., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Sexual reproduction is a key process influencing the evolution and adaptation of animals, plants, and many eukaryotic microorganisms, such as fungi. However, the sequential cell biology of fertilization and the associated nuclear dynamics after plasmogamy are poorly understood in filamentous fungi. Using histone-fluorescent parental isolates, we tracked male and female nuclei during fertilization in the model ascomycete Neurospora crassa using live-cell imaging. This study unravels the behavior of trichogyne resident female nuclei and the extraordinary manner in which male nuclei migrate up the trichogyne to the protoperithecium. Our observations raise new fundamental questions about the modus operandi of nucleus movements during sexual reproduction, male and female nuclear identity, guidance of nuclei within the trichogyne and, unexpectedly, the avoidance of "polyspermy" in fungi. The spatiotemporal dynamics of male nuclei within the trichogyne following plasmogamy are also described, where the speed and the deformation of male nuclei are of the most dramatic observed to date in a living organism. IMPORTANCE Using live-cell fluorescence imaging, for the first time we have observed live male and female nuclei during sexual reproduction in the model fungus Neurospora crassa. This study reveals the specific behavior of resident female nuclei within the trichogyne (the female organ) after fertilization and the extraordinary manner in which male nuclei migrate across the trichogyne toward their final destination, the protoperithecium, where karyogamy takes place. Importantly, the speed and deformation of male nuclei were found to be among the most dramatic ever observed in a living organism. Furthermore, we observed that entry of male nuclei into protoperithecia may block the entry of other male nuclei, suggesting that a process analogous to polyspermy avoidance could exist in fungi. Our live-cell imaging approach opens new opportunities for novel research on cell-signaling during sexual reproduction in fungi and, on a broader scale, nuclear dynamics in eukaryotes.

Understanding the low-temperature pure state structure of spin glasses remains an open problem in the field of statistical mechanics of disordered systems. Here we study Monte Carlo dynamics, performing simulations of the growth of correlations following a quench from infinite temperature to a temperature well below the spin-glass transition temperature T&#95;{c} for a one-dimensional Ising spin-glass model with diluted long-range interactions. In this model, the probability P&#95;{ij} that an edge {i,j} has nonvanishing interaction falls as a power law with chord distance, P&#95;{ij}∝1/R&#95;{ij}^{2σ}, and we study a range of values of σ with 1/2<σ<1. We consider a correlation function C&#95;{4}(r,t). A dynamic correlation length that shows power-law growth with time ξ(t)∝t^{1/z} can be identified in the data and, for large time t, C&#95;{4}(r,t) decays as a power law r^{-α&#95;{d}} with distance r when r≪ξ(t). The calculation can be interpreted in terms of the maturation metastate averaged Gibbs state, or MMAS, and the decay exponent α&#95;{d} differentiates between a trivial MMAS (α&#95;{d}=0), as expected in the droplet picture of spin glasses, and a nontrivial MMAS (α&#95;{d}≠0), as in the replica-symmetry-breaking (RSB) or chaotic pairs pictures. We find nonzero α&#95;{d} even in the regime σ>2/3 which corresponds to short-range systems below six dimensions. For σ<2/3, the decay exponent α&#95;{d} follows the RSB prediction for the decay exponent α&#95;{s}=3-4σ of the static metastate, consistent with a conjectured statics-dynamics relation, while it approaches α&#95;{d}=1-σ in the regime 2/3<σ<1; however, it deviates from both lines in the vicinity of σ=2/3.

Background: Radiation-induced mucositis (RIM) pain confers substantial morbidity for head and neck cancer (HNC) patients undergoing radiotherapy alone (RT) or chemoradiotherapy (CRT), often reducing treatment compliance. However, no standard currently exists for the treatment of RIM, and high dose opioid therapy, with its associated side effects and increased risk for chronic opioid use, remains the cornerstone of HNC pain management. The goal of this randomized clinical trial is to compare multimodal analgesia using analgesic medications with different mechanisms of action, to the institutional standard of opioid analgesia alone, in order to ascertain the optimal analgesic regimen for the management of RIM pain in HNC patients., Methods: In this open-label, single-institution, non-inferiority, randomized clinical trial, sixty-two patients with mucosal head and neck malignancies treated with curative-intent radiation will be randomized in a 1:1 ratio, stratified by RT or CRT, between Arm 1: opioid analgesia alone as per the institutional standard, or Arm 2: multimodal analgesia using Pregabalin, Acetaminophen, and Naproxen, in addition to opioids, if required. The primary endpoint is the average 11-Numeric Rating Scale (11-NRS) score for pain during the last week of radiation treatment. Secondary endpoints include: average weekly opioid use, duration of opioid requirement, average daily 11-NRS score for pain, average weekly opioids dispensed, quality of life, hospitalizations for analgesic medication-induced complications, time to feeding tube insertion, weight loss, toxicity, treatment interruptions, and death within 3 months of completing RT treatment. Patients are eligible once analgesia is required for moderate 4/10 pain., Discussion: This study will assess the efficacy and safety of multimodal analgesia and its impact on opioid requirements, clinical outcomes, and quality of life, as a potential new standard treatment for RIM pain in HNC patients undergoing definitive RT or CRT., Trial Registration: ClinicalTrials.gov Identifier: NCT04221165 . Date of registration: January 9, 2020. Appendix 2 reports the World Health Organization trial registration dataset.

Many bacterial species readily develop biofilms that act as a protective matrix against external challenge, e.g., from antimicrobial treatment. Therefore, biofilms are often responsible for persistent and recurring infections. Established methods for studying biofilms are either destructive or focus on the biofilm's surface. A non-destructive method that is sensitive to the underside of the biofilm is highly desirable, as it allows studying the penetration of antibiotics through the film. Here, we demonstrate that the high surface sensitivity of resonant hyperspectral imaging provides this capability. The method allows us to monitor the early stages of Escherichia coli biofilm formation, cell attachment and microcolony formation, in-situ and in real-time. We study the response of the biofilm to a number of different antibiotics and verify our observations using confocal microscopy. Based on this ability to closely monitor the surface-bound cells, resonant hyperspectral imaging gives new insights into the antimicrobial resistance of biofilms.

Background: Transoral surgery (TOS), particularly transoral robotic surgery (TORS) has become the preferred modality in the United States for the treatment of early stage oropharyngeal cancer, largely due to assumptions of fewer toxicities and improved quality of life compared to primary radiotherapy (RT). However, these assumptions are based on retrospective analysis, a subset of which utilize primary RT groups not limited to T1-2 stage tumors for which transoral robotic surgery is FDA approved. Thus, there is potential for underestimating survival and overestimating toxicity, including treatment related mortality, in primary RT., Methods: Consecutive cases of early T-stage (T1-T2) oropharyngeal cancer presenting to the London Health Sciences Centre between 2014 and 2018 treated with RT or chemoradiation (CRT) were reviewed. Patient demographics, treatment details, survival outcomes and toxicity were collected. Toxicities were retrospectively graded using the Common Terminology Criteria for Adverse Events criteria., Results: A total of 198 patients were identified, of which 82% were male and 73% were HPV-positive. Sixty-eight percent of patients experienced a grade 2 toxicity, 48% a grade 3 and 4% a grade 4. The most frequent toxicities were dysphagia, neutropenia and ototoxicity. The rates of gastrostomy tube dependence at 1 and 2 years were 2.5% and 1% respectively. There were no grade 5 (fatal) toxicities. HPV-positive patients experienced improved 5-year overall survival (86% vs 64%, p = 0.0026)., Conclusions: Primary RT or CRT provides outstanding survival for early T-stage disease, with low rates of severe toxicity and feeding tube dependence. This study provides a reference for comparison for patients treated with primary transoral surgery.

Purpose: Opioid addiction is a major public health concern. Chronic opioid use (COU) patterns after radiation for head and neck cancer (HNC) remain poorly understood. The aim of this study was to estimate the prevalence of COU and to identify its risk factors in patients with HNC undergoing curative-intent radiation therapy (RT) or chemoradiotherapy (CRT)., Methods and Materials: We performed a systematic review and meta-analysis using the PubMed (Medline), EMBASE, and Cochrane Library databases, queried from dates of inception until January 2020. COU was defined as persistent use of opioids ≥ 3 months after treatment completion. Meta-analyses were performed using random effects models. Heterogeneity was assessed using the I 2 value., Results: Seven retrospective studies, reporting on 1841 patients, met the inclusion criteria. Median age was 59.4 (range: 56.0-62.0) years with 1343 (72.9%) men and 498 (27.1%) women. Primary tumor locations included oropharynx (n = 891, 48.4%), oral cavity (n = 533, 29.0%), larynx (n = 93, 5.1%), hypopharynx (n = 32, 1.7%), and nasopharynx (n = 29, 1.6%). Eight hundred fifty-four (46.0%) patients had stage I/II and 952 (50.3%) had stage III-IV disease. Three hundred one (16.3%) patients had RT alone, 738 (40.1%) received CRT, and 594 (32.3%) underwent surgery followed by adjuvant RT/CRT. The proportion of patients with HNC who developed COU post-RT/CRT was 40.7% at 3 months (95% confidence interval [CI]: 22.6%-61.7%; I 2 = 97.1%) and 15.5% at 6 months (95% CI: 7.3%-29.7%; I 2 = 94.3%). Oropharyngeal malignancies had the highest rate of COU based on primary tumor location (46.6%; 95% CI: 30.8%-63.1%; P < .0001). High proportions of COU were found in patients with a history of psychiatric disorder(s) (61.7%), former/current alcohol abuse (53.9%), and opioid requirements before radiation treatment (51.6%; P = .035)., Conclusions: A significant proportion of patients who undergo RT for HNC suffer from COU. High-risk factors for COU include an oropharyngeal primary, history of psychiatric disorder, former/current alcohol abuse, and pre-treatment opioid use. New strategies to mitigate COU are needed., (© 2020 The Author(s).)

Background: Head-and-neck cancers (hncs) often present at an advanced stage, leading to poor outcomes. Late presentation might be attributable to patient delays (reluctance to seek treatment, for instance) or provider delays (misdiagnosis, prolonged wait time for consultation, for example). The objective of the present study was to examine the length and cause of such delays in a Canadian universal health care setting., Methods: Patients presenting for the first time to the hnc multidisciplinary team (mdt) with a biopsy-proven hnc were recruited to this study. Patients completed a survey querying initial symptom presentation, their previous medical appointments, and length of time between appointments. Clinical and demographic data were collected for all patients., Results: The average time for patients to have their first appointment at the mdt clinic was 15.1 months, consisting of 3.9 months for patients to see a health care provider (hcp) for the first time since symptom onset and 10.7 months from first hcp appointment to the mdt clinic. Patients saw an average of 3 hcps before the mdt clinic visit (range: 1-7). No significant differences in time to presentation were found based on stage at presentation or anatomic site., Conclusions: At our tertiary care cancer centre, a patient's clinical pathway to being seen at the mdt clinic shows significant delays, particularly in the time from the first hcp visit to mdt referral. Possible methods to mitigate delay include education about hnc for patients and providers alike, and a more streamlined referral system., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none., (2020 Multimed Inc.)

Purpose: Female patients with breast cancer frequently develop arthralgia when treated with aromatase inhibitors (AI). Although the mechanism of AI-induced arthralgia is unknown, potential biomarkers have been identified. The purpose of this study was to investigate the clinical and genetic predictors of AI-induced arthralgia in a prospective cohort of patients with estrogen receptor-positive breast cancer., Methods: One hundred and ninety-six patients were enrolled at initiation of AI therapy with either letrozole or anastrozole. Patients completed two validated self-report questionnaires assessing pain, stiffness, and physical function at baseline, and repeated the questionnaires at two and at six months after the initiation of treatment with an AI. Germline DNA of all patients was genotyped for seven single-nucleotide polymorphisms (SNPs) previously identified by genetic screens and genome-wide association studies as associated with AI-induced arthralgia., Results: More than 50% of the study group experienced arthralgia symptoms. Genetic analysis revealed that four SNPs, in CYP19A1 (rs4775936) and ESR1 (rs9322336, rs2234693, rs9340799), were associated with the development of arthralgia (adjusted P = 0.016, 0.018, 0.017, 0.047). High body mass index (BMI) was also associated with the development of arthralgia symptoms (adjusted P = 0.001). Patients prescribed letrozole were significantly more likely to develop arthralgia than patients on anastrozole (P = 0.018), and also more likely to discontinue AI therapy due to arthralgia. The CYP19A1 (rs4775936) SNP was significantly associated with discontinuation of therapy due to intolerable arthralgia., Conclusions: Our results suggested that BMI and AI drug (letrozole versus anastrozole) were clinical predictors of arthralgia, while genetic variants rs4775936, rs9322336, rs2234693, and rs9340799 were genetic predictors of AI-induced arthralgia. Significantly, rs4775936 was also a predictor of discontinuation of therapy.

Background: Patients with resected oral cavity squamous cell carcinoma (OCSCC) are often treated with adjuvant radiation (RT) ± concomitant chemotherapy based on pathological findings. Standard RT volumes include all surgically dissected areas, including the tumour bed and dissected neck. RT has significant acute and long-term toxicities including odynophagia, dysphagia, dermatitis and fibrosis. The goal of this study is to assess the rate of regional failure with omission of radiation to the surgically dissected pathologically node negative (pN0) hemi-neck(s) compared to historical control, and to compare oncologic outcomes, toxicity, and quality of life (QoL) profiles between standard RT volumes and omission of RT to the pN0 neck., Methods: This is a multicentre phase II study randomizing 90 patients with T1-4 N0-2 OCSCC with at least one pN0 hemi-neck in a 1:2 ratio between standard RT volumes and omission of RT to the pN0 hemi-neck(s). Patients will be stratified based on overall nodal status (nodal involvement vs. no nodal involvement) and use of concurrent chemotherapy. The primary endpoint is regional failure in the pN0 hemi-neck(s); we hypothesize that a 2-year regional recurrence of 20% or less will be achieved. Secondary endpoints include overall and progression-free survival, local recurrence, rate of salvage therapy, toxicity and QoL., Discussion: This study will provide an assessment of omission of RT to the dissected pN0 hemi-neck(s) on oncologic outcomes, QoL and toxicity. Results will inform the design of future definitive phase III trials., Trial Registration: Clinicaltrials.gov identifier: NCT03997643 . Date of registration: June 25, 2019, Current version: 2.0 on July 11 2020.

Anxiety and irritability symptoms frequently co-occur in children with Attention-Deficit/Hyperactivity Disorder (ADHD). This study aims to investigate whether irritability and anxiety are uniquely associated with performance on measures of cognitive functioning in children with ADHD and whether these associations hold when accounting for confounding variables. Baseline data was used from a randomised controlled trial of cognitive behavioural therapy for anxiety in children with ADHD (N = 219, 8-13 years). Anxiety was assessed using the child- and parent-reported Spence Children's Anxiety Scale, while irritability was assessed using the parent-reported Affective Reactivity Index. Children completed the National Institutes of Health Toolbox - Cognition Battery. Higher symptoms of anxiety were uniquely associated with performance on the Dimensional Card Change Sort Test (β = -2.75, confidence interval (CI) [-4.97, -.52], p = .02) and the List Sort Working Memory Test (β = -2.57, CI [-4.43, -.70], p = .01), while higher symptoms of irritability were negatively associated with Picture Vocabulary Test (β = -2.00, CI [-3.83, -.16], p = .03). These associations did not survive correction for multiple comparisons. There was little evidence of an association between anxiety or irritability symptoms and cognitive functioning. Frequent co-occurrence of anxiety and irritability suggests clinicians working with children with ADHD should assess co-morbid symptom profiles to inform the provision of optimum care.

The de Almeida-Thouless (AT) line is the phase boundary in the temperature-magnetic field plane of an Ising spin glass at which a continuous (i.e., second-order) transition from a paramagnet to a replica-symmetry-breaking (RSB) phase occurs, according to mean-field theory. Here, using field-theoretic perturbative renormalization group methods on the Bray-Roberts reduced Landau-Ginzburg-type theory for a short-range Ising spin glass in space of dimension d, we show that at nonzero magnetic field the nature of the corresponding transition is modified as follows: (a) For d-6 small and positive, with increasing field on the AT line, first, the ordered phase just below the transition becomes the so-called one-step RSB, instead of the full RSB that occurs in mean-field theory; the transition on the AT line remains continuous with a diverging correlation length. Then at a higher field, a tricritical point separates the latter transition from a quasi-first-order one, that is one at which the correlation length does not diverge, and there is a jump in part of the order parameter, but no latent heat. The location of the tricritical point tends to zero as d→6^{+}. (b) For d≤6, we argue that the quasi-first-order transition could persist down to arbitrarily small nonzero fields, with a transition to full RSB still expected at lower temperature. Whenever the quasi-first-order transition occurs, it is at a higher temperature than the AT transition would be for the same field, preempting it as the temperature is lowered. These results may explain the reported absence of a diverging correlation length in the presence of a magnetic field in low-dimensional spin glasses in some simulations and in high-temperature series expansions. We also draw attention to the similarity of the "dynamically frozen" state, which occurs at temperatures just above the quasi-first-order transition, and the "metastate-average state" of the one-step RSB phase, and discuss the issue of the number of pure states in either.

Background: Patients with human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) have substantially better treatment response and overall survival (OS) than patients with HPV-negative disease. Treatment options for HPV+ OPC can involve either a primary radiotherapy (RT) approach (± concomitant chemotherapy) or a primary surgical approach (± adjuvant radiation) with transoral surgery (TOS). These two treatment paradigms have different spectrums of toxicity. The goals of this study are to assess the OS of two de-escalation approaches (primary radiotherapy and primary TOS) compared to historical control, and to compare survival, toxicity and quality of life (QOL) profiles between the two approaches., Methods: This is a multicenter phase II study randomizing one hundred and forty patients with T1-2 N0-2 HPV+ OPC in a 1:1 ratio between de-escalated primary radiotherapy (60 Gy) ± concomitant chemotherapy and TOS ± de-escalated adjuvant radiotherapy (50-60 Gy based on risk factors). Patients will be stratified based on smoking status (< 10 vs. ≥ 10 pack-years). The primary endpoint is OS of each arm compared to historical control; we hypothesize that a 2-year OS of 85% or greater will be achieved. Secondary endpoints include progression free survival, QOL and toxicity., Discussion: This study will provide an assessment of two de-escalation approaches to the treatment of HPV+ OPC on oncologic outcomes, QOL and toxicity. Results will inform the design of future definitive phase III trials., Trial Registration: Clinicaltrials.gov identifier: NCT03210103. Date of registration: July 6, 2017, Current version: 1.3 on March 15, 2019.

Background: Is posttreatment functional status prognostic of overall survival in patients with head and neck cancer (HNC)., Methods: In an HNC clinical trial, 495 patients had two posttreatment functional assessments measuring diet, public eating, and speech within 6 months. Patients were grouped by impairment (highly, moderately, modestly, or not impaired) and determined if they improved, declined, or did not change from the first assessment to the second. Multivariable Cox models estimated overall mortality., Results: Across all three scales, the change in posttreatment patient function strongly predicted overall survival. In diet, patients who declined to highly impaired had three times the mortality of patients who were not impaired at both assessments (hazard ratio [HR] = 3.60; 95% confidence interval, 2.02-6.42). For patients improving from highly impaired, mortality was statistically similar to patients with no impairment (HR = 1.38; 95% CI, 0.82-2.31)., Conclusions: Posttreatment functional status is a strong prognostic marker of survival in patients with HNC., (© 2019 Wiley Periodicals, Inc.)

Background: Transoral robotic surgery (TORS) with concurrent neck dissection has supplanted radiotherapy in the USA as the most common treatment for oropharyngeal squamous cell carcinoma (OPSCC), yet no randomised trials have compared these modalities. We aimed to evaluate differences in quality of life (QOL) 1 year after treatment., Methods: The ORATOR trial was an investigator-initiated, multicentre, international, open-label, parallel-group, phase 2, randomised study. Patients were enrolled at six hospitals in Canada and Australia. We randomly assigned (1:1) patients aged 18 years or older, with Eastern Cooperative Oncology Group scores of 0-2, and with T1-T2, N0-2 (≤4 cm) OPSCC tumour types to radiotherapy (70 Gy, with chemotherapy if N1-2) or TORS plus neck dissection (with or without adjuvant chemoradiotherapy, based on pathology). Following stratification by p16 status, patients were randomly assigned using a computer-generated randomisation list with permuted blocks of four. The primary endpoint was swallowing-related QOL at 1 year as established using the MD Anderson Dysphagia Inventory (MDADI) score, powered to detect a 10-point improvement (a clinically meaningful change) in the TORS plus neck dissection group. All analyses were done by intention to treat. This study is registered with ClinicalTrials.gov (NCT01590355) and is active, but not currently recruiting., Findings: 68 patients were randomly assigned (34 per group) between Aug 10, 2012, and June 9, 2017. Median follow-up was 25 months (IQR 20-33) for the radiotherapy group and 29 months (23-43) for the TORS plus neck dissection group. MDADI total scores at 1 year were mean 86·9 (SD 11·4) in the radiotherapy group versus 80·1 (13·0) in the TORS plus neck dissection group (p=0·042). There were more cases of neutropenia (six [18%] of 34 patients vs none of 34), hearing loss (13 [38%] vs five [15%]), and tinnitus (12 [35%] vs two [6%]) reported in the radiotherapy group than in the TORS plus neck dissection group, and more cases of trismus in the TORS plus neck dissection group (nine [26%] vs one [3%]). The most common adverse events in the radiotherapy group were dysphagia (n=6), hearing loss (n=6), and mucositis (n=4), all grade 3, and in the TORS plus neck dissection group, dysphagia (n=9, all grade 3) and there was one death caused by bleeding after TORS., Interpretation: Patients treated with radiotherapy showed superior swallowing-related QOL scores 1 year after treatment, although the difference did not represent a clinically meaningful change. Toxicity patterns differed between the groups. Patients with OPSCC should be informed about both treatment options., Funding: Canadian Cancer Society Research Institute Grant (#701842), Ontario Institute for Cancer Research Clinician-Scientist research grant, and the Wolfe Surgical Research Professorship in the Biology of Head and Neck Cancers grant., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: Accurate contouring in head and neck cancer (HNC) is critical. International consensus guidelines recommend the 5 + 5 mm rule for expansions around the primary tumor, wherein high- and low-dose clinical target volumes (CTV-P1 and CTV-P2, respectively) are created using successive 5 mm expansions on the gross tumor volume. To our knowledge, the necessity of a low-dose CTV-P2 has never been assessed; therefore, we evaluated the dosimetric impact of adding a CTV-P2 expansion using the 5 + 5 mm rule compared with contouring with a high-dose CTV-P1 alone., Methods and Materials: A retrospective study of clinically delivered (chemo)radiation therapy treatment plans for HNC was conducted. All patients were treated with 70 Gy in 35 fractions using volumetric modulated arc therapy in a single phase. CTV-P2 was retrospectively contoured per guidelines as a 5 mm expansion on CTV-P1 from the clinical plan, carving off specified barriers to spread. We used a 5 mm planning target volume (PTV) expansion. Our primary outcome was whether 95% of the volume of the PTV for the CTV-P2 contour (ie, PTV-P2) received at least 56 Gy. To assess dose falloff, the coverage of a PTV ring structure was created by subtracting PTV-P1 from PTV-P2., Results: Twenty-seven patients from 4 HNC subsites (base of tongue, tonsil, hypopharynx, and supraglottic larynx) were included. In all 108 treatment plans, at least 95% of the PTV-P2 structure received at least 56 Gy. The minimum volume of the PTV-P2 structure receiving at least 56 Gy was 97.4%. Eight of 108 treatment plans had borderline coverage of the PTV ring substructure alone., Conclusions: Adding a CTV-P2 structure using the 5 + 5 mm rule had no dosimetric impact, adds contouring time, adds treatment planning complexity, and could potentially introduce errors. The 5 + 5 mm rule may have value in other settings, such as when smaller PTV margins are used, and warrants further evaluation with prospective or randomized studies., (© 2019 The Author(s).)

Actinomycete bacteria use polyprenol phosphate mannose as a lipid-linked sugar donor for extra-cytoplasmic glycosyl transferases that transfer mannose to cell envelope polymers, including glycoproteins and glycolipids. Strains of Streptomyces coelicolor with mutations in the gene ppm1, encoding polyprenol phosphate mannose synthase, and in pmt, encoding a protein O-mannosyltransferase, are resistant to phage ϕC31 and have greatly increased susceptibility to some antibiotics, including vancomycin. In this work, second-site suppressors of the vancomycin susceptibility were isolated. The suppressor strains fell into two groups. Group 1 strains had increased resistance to vancomycin, teicoplanin and β-lactams, and had mutations in the two-component sensor regulator system encoded by vanSR, leading to upegulation of the vanSRJKHAX cluster. Group 2 strains only had increased resistance to vancomycin and these mostly had mutations in sco2592 or sco2593, genes that are derepressed in the presence of phosphate and are likely to be required for the synthesis of a phosphate-containing extracellular polymer. In some suppressor strains the increased resistance was only observed in media with limited phosphate (mimicking the phenotype of wild-type S. coelicolor), but two strains, DT3017&#95;R21 (ppm1 - vanR - ) and DT3017&#95;R15 (ppm1 - sco2593 - ), retained resistance on media with high phosphate content. These results support the view that vancomycin resistance in S. coelicolor is a trade-off between mechanisms that confer resistance and at least one that interferes with resistance mediated through the sco2594-sco2593-sco2592 operon.

Purpose: The aromatase inhibitor (AI) letrozole is a first-line drug in the adjuvant treatment of breast cancer in postmenopausal women. Adherence to AI therapy, including letrozole, remains problematic due to the development of debilitating AI-induced arthralgia. Letrozole is metabolized in the liver by CYP2A6. It remains unknown if plasma letrozole levels or CYP2A6 genetic variation is associated with the development of arthralgia., Methods: We enrolled 126 female breast cancer patients initiated on letrozole therapy and prospectively collected blood samples at baseline and two follow-up time points to determine letrozole plasma concentrations and CYP2A6 genotype. At each visit, participants completed two validated questionnaires to assess the severity of arthralgia symptoms., Results: More than half (55%) of patients experienced a significant increase in their arthralgia symptoms after initiation of treatment. The clinical variables of body mass index (P = 0.0003) and age (P = 0.0430) were negatively and positively associated with plasma letrozole concentrations, respectively. CYP2A6 genotype was significantly associated with letrozole levels (P < 0.0001), and increased plasma letrozole levels were observed in patients with CYP2A6 reduced-function genotypes. Plasma levels of letrozole and CYP2A6 genotype were not significantly associated with a change in pain score from baseline., Conclusions: CYP2A6 genotype was a significant predictor of letrozole plasma levels, but was not associated with the development of arthralgia.

Background: Most published genome sequences are drafts, and most are dominated by computational gene prediction. Draft genomes typically incorporate considerable sequence data that are not assigned to chromosomes, and predicted genes without quality confidence measures. The current Actinidia chinensis (kiwifruit) 'Hongyang' draft genome has 164 Mb of sequences unassigned to pseudo-chromosomes, and omissions have been identified in the gene models., Results: A second genome of an A. chinensis (genotype Red5) was fully sequenced. This new sequence resulted in a 554.0 Mb assembly with all but 6 Mb assigned to pseudo-chromosomes. Pseudo-chromosomal comparisons showed a considerable number of translocation events have occurred following a whole genome duplication (WGD) event some consistent with centromeric Robertsonian-like translocations. RNA sequencing data from 12 tissues and ab initio analysis informed a genome-wide manual annotation, using the WebApollo tool. In total, 33,044 gene loci represented by 33,123 isoforms were identified, named and tagged for quality of evidential support. Of these 3114 (9.4%) were identical to a protein within 'Hongyang' The Kiwifruit Information Resource (KIR v2). Some proportion of the differences will be varietal polymorphisms. However, as most computationally predicted Red5 models required manual re-annotation this proportion is expected to be small. The quality of the new gene models was tested by fully sequencing 550 cloned 'Hort16A' cDNAs and comparing with the predicted protein models for Red5 and both the original 'Hongyang' assembly and the revised annotation from KIR v2. Only 48.9% and 63.5% of the cDNAs had a match with 90% identity or better to the original and revised 'Hongyang' annotation, respectively, compared with 90.9% to the Red5 models., Conclusions: Our study highlights the need to take a cautious approach to draft genomes and computationally predicted genes. Our use of the manual annotation tool WebApollo facilitated manual checking and correction of gene models enabling improvement of computational prediction. This utility was especially relevant for certain types of gene families such as the EXPANSIN like genes. Finally, this high quality gene set will supply the kiwifruit and general plant community with a new tool for genomics and other comparative analysis.

Actinomycete bacteria use polyprenol phosphate mannose as a lipid linked sugar donor for extra-cytoplasmic glycosyl transferases that transfer mannose to cell envelope polymers, including glycoproteins and glycolipids. We showed recently that strains of Streptomyces coelicolor with mutations in the gene ppm1 encoding polyprenol phosphate mannose synthase were both resistant to phage φC31 and have greatly increased susceptibility to antibiotics that mostly act on cell wall biogenesis. Here we show that mutations in the genes encoding enzymes that act upstream of Ppm1 in the polyprenol phosphate mannose synthesis pathway can also confer phage resistance and antibiotic hyper-susceptibility. GDP-mannose is a substrate for Ppm1 and is synthesised by GDP-mannose pyrophosphorylase (GMP; ManC) which uses GTP and mannose-1-phosphate as substrates. Phosphomannomutase (PMM; ManB) converts mannose-6-phosphate to mannose-1-phosphate. S. coelicolor strains with knocked down GMP activity or with a mutation in sco3028 encoding PMM acquire phenotypes that resemble those of the ppm1 - mutants i.e. φC31 resistant and susceptible to antibiotics. Differences in the phenotypes of the strains were observed, however. While the ppm1 - strains have a small colony phenotype, the sco3028 :: Tn5062 mutants had an extremely small colony phenotype indicative of an even greater growth defect. Moreover we were unable to generate a strain in which GMP activity encoded by sco3039 and sco4238 is completely knocked out, indicating that GMP is also an important enzyme for growth. Possibly GDP-mannose is at a metabolic branch point that supplies alternative nucleotide sugar donors.

The de Almeida-Thouless (AT) line in Ising spin glasses is the phase boundary in the temperature T and magnetic field h plane below which replica symmetry is broken. Using perturbative renormalization group (RG) methods, we show that, when the dimension d of space is just above six, there is a multicritical point (MCP) on the AT line, which separates a low-field regime, in which the critical exponents have mean-field values, from a high-field regime, where the RG flows run away to infinite coupling strength; as d approaches six from above, the MCP approaches the zero-field critical point exponentially in 1/(d-6). Thus, on the AT line, perturbation theory for the critical properties breaks down at a sufficiently large magnetic field even above 6 dimensions, as well as for all nonzero fields when d≤6, as was known previously. We calculate the exponents at the MCP to first order in ϵ=d-6>0. The fate of the MCP as d increases from just above six to infinity is not known.

Polyprenol phosphate mannose (PPM) is a lipid-linked sugar donor used by extra-cytoplasmic glycosyl tranferases in bacteria. PPM is synthesized by polyprenol phosphate mannose synthase, Ppm1, and in most Actinobacteria is used as the sugar donor for protein O-mannosyl transferase, Pmt, in protein glycosylation. Ppm1 and Pmt have homologues in yeasts and humans, where they are required for protein O-mannosylation. Actinobacteria also use PPM for lipoglycan biosynthesis. Here we show that ppm1 mutants of Streptomyces coelicolor have increased susceptibility to a number of antibiotics that target cell wall biosynthesis. The pmt mutants also have mildly increased antibiotic susceptibilities, in particular to β-lactams and vancomycin. Despite normal induction of the vancomycin gene cluster, vanSRJKHAX, the pmt and ppm1 mutants remained highly vancomycin sensitive indicating that the mechanism of resistance is blocked post-transcriptionally. Differential RNA expression analysis indicated that catabolic pathways were downregulated and anabolic ones upregulated in the ppm1 mutant compared to the parent or complemented strains. Of note was the increase in expression of fatty acid biosynthetic genes in the ppm1 - mutant. A change in lipid composition was confirmed using Raman spectroscopy, which showed that the ppm1 - mutant had a greater relative proportion of unsaturated fatty acids compared to the parent or the complemented mutant. Taken together, these data suggest that an inability to synthesize PPM (ppm1) and loss of the glycoproteome (pmt - mutant) can detrimentally affect membrane or cell envelope functions leading to loss of intrinsic and, in the case of vancomycin, acquired antibiotic resistance.

We consider the one-dimensional model of a spin glass with independent Gaussian-distributed random interactions, which have mean zero and variance 1/|i-j|^{2σ}, between the spins at sites i and j for all i≠j. It is known that, for σ>1, there is no phase transition at any nonzero temperature in this model. We prove rigorously that, for σ>3/2, any translation-covariant Newman-Stein metastate for the ground states (i.e., the frequencies with which distinct ground states are observed in finite-size samples in the limit of infinite size, for given disorder) is trivial and unique. In other words, for given disorder and asymptotically at large sizes, the same ground state, or its global spin flip, is obtained (almost) always. The proof consists of two parts: One is a theorem (based on one by Newman and Stein for short-range two-dimensional models), valid for all σ>1, that establishes triviality under a convergence hypothesis on something similar to the energies of domain walls and the other (based on older results for the one-dimensional model) establishes that the hypothesis is true for σ>3/2. In addition, we derive heuristic scaling arguments and rigorous exponent inequalities which tend to support the validity of the hypothesis under broader conditions. The constructions of various metastates are extended to all values σ>1/2. Triviality of the metastate in bond-diluted power-law models for σ>1 is proved directly.

An aerobic, Gram-stain negative, short rod-shaped and motile strain, 36-5-1 T , was isolated from the roots of Nitraria sibirica in Zhangye city, Gansu province, north-west of China. Phylogenetic analysis based on the 16S rRNA gene sequence and two housekeeping genes (glnA and atpD) indicated that the strain represents a novel species closely related to the Devosia, Rhizobium and Devosia genera with 98.3, 96.2 and 91.1% similarities, respectively. The strain 36-5-1 T contained Q-10 as the predominant ubiquinone and 16:0 (36.8%) as the major fatty acid; a large amount of unidentified glycolipid, diphosphatidylglycerol, phosphatidylglycerol and a small amount of unidentified polar lipids were present as polar lipids. In addition, the G+C content of the genomic DNA was 61.7 mol% and the DNA-DNA hybridization with type strains Devosia geojensis BD-c194 T and Devosia pacifica NH131 T 44.1 ± 1.1 and 40.2 ± 1.7, respectively. Based on chemotaxonomic data and molecular properties, strain 36-5-1 T represents a novel species within the genus Devosia, for which the name Devosia nitraria sp. nov. is proposed. The type strain is 36-5-1 T (=CGMCC1.15704 T =NBRC112416 T) .

Objectives/hypothesis: Common endpoints in reporting the outcomes for early glottic cancer do not highlight the importance of organ preservation. We evaluated the treatment outcomes among patients with T1aN0 laryngeal cancer with laryngectomy-free disease-specific survival (LFS-DSS), which is defined as time to total laryngectomy or time to death from cancer cause, against all other endpoints., Study Design: Outcome research on an institutional database., Methods: A retrospective review covered all consecutive patients from 2003 to 2013. Patients with T1a laryngeal squamous cell carcinoma (SCC) were offered the options of either radiation treatment (RT) or transoral laser microsurgery (TLM). Tumor control, survival outcomes, standard definition laryngectomy-free survival (LFS), and LFS-DSS were calculated., Results: There were 105 patients, of whom 53 were treated with TLM and 52 were treated with RT. There were 11 recurrences within the TLM group, of which four were successfully salvaged with repeated TLM and two were salvaged with RT. Among the four recurrences within the RT group, all four patients had salvage total laryngectomies. The 5-year overall survival for patients treated with TLM versus RT was 86% versus 85% (P = .887), disease-free survival was 69% versus 78% (P = .151), LFS was 65% versus 77% (P = .198), LFS-DSS was 100% versus 88% (P = .030), and ultimate locoregional control was 100% in both groups., Conclusions: Patients with T1aN0 glottic SCC treated with RT or TLM have similar survival outcomes. Patients with T1a tumor treated with TLM have better organ preservation compared to RT, when measured with LFS-DSS., Level of Evidence: 4. Laryngoscope, 127:1322-1327, 2017., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: Recently our group developed a unified intensity-modulated arc therapy (UIMAT) technique which allows for the simultaneous inverse-optimization and the combined delivery of volume-modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT). The aim of this study was to evaluate the dosimetric benefits of UIMAT plans for radiation treatment of complex head-and-neck cancer cases., Methods and Materials: A retrospective treatment planning study was performed on 30 head-and-neck cases, 15 of which were treated clinically with VMAT while the other 15 were treated with step-and-shoot IMRT. These cases were re-planned using our UIMAT technique and the results were compared with the clinically delivered plans. Plans were assessed in terms of clinically relevant metrics describing target volume coverage, dose conformity, and the sparing of organs at risk., Results: When compared to stand-alone VMAT or IMRT, UIMAT plans offered slightly better tumor volume coverage (Median D95: 98.1% vs. 97.5%, p=0.01) and similar dose conformity (Median CI: 0.69 vs. 0.69, p=0.09). More significantly, UIMAT plans had substantially lower doses to all organs at risk, including the spinal cord (Median D2%: 29.9Gy vs. 35.6Gy, p<0.01), brainstem (Median D2%: 21.2Gy vs. 25.6Gy, p<0.01), left parotid (Median DMean: 26.1Gy vs. 28.0Gy, p<0.01), and right parotid (Median DMean: 23.6Gy vs. 27.2Gy, p<0.01). The reduction in OAR doses did not result from the redistribution of dose to unspecified tissue. Furthermore, UIMAT plans can be delivered with comparable delivery times to VMAT (Median time: 135s vs. 168s, p=0.394) but with fewer monitor units (Median MU: 486 vs. 635, p<0.01)., Conclusions: Compared to stand-alone IMRT or VMAT, UIMAT was demonstrated to have a dosimetric advantage for the radiation treatment of head-and-neck cancer., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Most casinos owned by sovereign American Indian nations allow smoking, even in U.S. states such as California where state laws restrict workplace smoking. Collaborations between casinos and public health workers are needed to promote smoke-free policies that protect workers and patrons from secondhand tobacco smoke (SHS) exposure and risks. Over seven years, a coalition of public health professionals provided technical assistance to the Redding Rancheria tribe in Redding, California in establishing a smoke-free policy at the Win-River Resort and Casino. The coalition provided information to the casino general manager that included site-specific measurement of employee and visitor PM2.5 personal exposure, area concentrations of airborne nicotine and PM2.5, visitor urinary cotinine, and patron and staff opinions (surveys, focus groups, and a Town Hall meeting). The manager communicated results to tribal membership, including evidence of high SHS exposures and support for a smoke-free policy. Subsequently, in concert with hotel expansion, the Redding Rancheria Tribal Council voted to accept a 100% restriction of smoking inside the casino, whereupon PM2.5 exposure in main smoking areas dropped by 98%. A 70% partial-smoke-free policy was instituted ~1 year later in the face of revenue loss. The success of the collaboration in promoting a smoke-free policy, and the key element of air quality feedback, which appeared to be a central driver, may provide a model for similar efforts.

Hereditary angioedema (HAE) is a rare disease characterized by episodes of potentially life-threatening angioedema. For affected children in the United Kingdom, there are relatively few data regarding disease prevalence, service organization and the humanistic burden of the disease. To improve knowledge in these areas, we surveyed major providers of care for children with HAE. A questionnaire was sent to major paediatric centres to determine patient numbers, symptoms, diagnostic difficulties, management and available services. In addition, all patients at a single centre were given a questionnaire to determine the experiences of children and their families. Sixteen of 28 centres responded, caring for a total of 111 UK children. Seven children had experienced life-threatening crises. One-third of patients were on long-term prophylactic medication, including C1 inhibitor prophylaxis in four children. Eight centres reported patients who were initially misdiagnosed. Broad differences in management were noted, particularly regarding indications for long-term prophylaxis and treatment monitoring. We also noted substantial variation in the organization of services between centres, including the number of consultants contributing to patient care, the availability of specialist nurses, the availability of home therapy training and the provision of patient information. Ten of 12 patient/carer questionnaires were returned, identifying three common themes: the need to access specialist knowledge, the importance of home therapy and concerns around the direct effect of angioedema on their life. To our knowledge, this study represents the first dedicated survey of paediatric HAE services in the United Kingdom and provides useful information to inform the optimization of services., (© 2014 British Society for Immunology.)

Background: Induction chemotherapy followed by concurrent chemoradiation (CRT) (sequential therapy) has been evaluated in the treatment of locoregionally-advanced squamous cell cancer of the head and neck (LA-SCCHN), with docetaxel, cisplatin (P) and 5-flurouracil (F) shown to be superior to PF doublet. Nab-paclitaxel (A) is a novel albumin-bound paclitaxel with a superior therapeutic index to docetaxel., Methods: A phase I trial [Clinical trials.gov identifier NCT00731380] to assess the safety and efficacy of nab-paclitaxel+cisplatin+5-fluorouracil (APF) as induction chemotherapy for three cycles, followed by concurrent carboplatin (area-under-curve (AUC) 1.5 weekly) with radiation therapy (RT) (70 Gy/35 fractions), was conducted using a 3+3 design in patients with previously untreated LA-SCCHN. Dose-limiting toxicities (DLTs) included: standard haematologic and non-haematologic toxicities, treatment delays, inability to complete ⩾95% of RT and skin/mucosal toxicity related to RT assessed from day 1 of treatment to 8 weeks after completion of CRT., Results: 17 patients with oropharyngeal cancer were enrolled in three dose levels, with 15 patients evaluable for DLT. The median age was 54 years (range, 44-65 years), 14 patients were male, and 11 patients' tumours were p16 positive and four negative. Grade 3/4 adverse events during APF (%total number of cycles) were hyponatraemia (14%) neutropenia (10%), lymphopaenia (4%) and thrombocytopenia (2%) during 49 evaluable APF cycles. Febrile neutropenia occurred during one cycle of treatment., Conclusion: The recommended phase 2 dose of APF is nab-paclitaxel 100mg/m(2) days 1 and 8, cisplatin 75 mg/mg(2) day 1 and 5-fluorouracil 1000 mg/m(2)/day×96 h days 1-4, every 3 weeks, for three cycles prior to CRT., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Parisi's formal replica-symmetry-breaking (RSB) scheme for mean-field spin glasses has long been interpreted in terms of many pure states organized ultrametrically. However, the early version of this interpretation, as applied to the short-range Edwards-Anderson model, runs into problems because as shown by Newman and Stein (NS) it does not allow for chaotic size dependence, and predicts non-self-averaging that cannot occur. NS proposed the concept of the metastate (a probability distribution over infinite-size Gibbs states in a given sample that captures the effects of chaotic size dependence) and a nonstandard interpretation of the RSB results in which the metastate is nontrivial and is responsible for what was called non-self-averaging. In this picture, each state drawn from the metastate has the ultrametric properties of the old theory, but when the state is averaged using the metastate, the resulting mixed state has little structure. This picture was constructed so as to agree both with the earlier RSB results and with rigorous results. Here we use the effective field theory of RSB, in conjunction with the rigorous definitions of pure states and the metastate in infinite-size systems, to show that the nonstandard picture follows directly from the RSB mean-field theory. In addition, the metastate-averaged state possesses power-law correlations throughout the low-temperature phase; the corresponding exponent ζ takes the value 4 according to the field theory in high dimensions d, and describes the effective fractal dimension of clusters of spins. Further, the logarithm of the number of pure states in the decomposition of the metastate-averaged state that can be distinguished if only correlations in a window of size W can be observed is of order W(d-ζ). These results extend the nonstandard picture quantitatively; we show that arguments against this scenario are inconclusive. More generally, in terms of Parisi's function q(x), if q(0)≠∫(0)(1)dxq(x), then the metastate is nontrivial. In an Appendix, we also prove rigorously that the metastate-averaged state of the Sherrington-Kirkpatrick model is a uniform distribution on all spin configurations at all temperatures.