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Background/aims: More than 99% of individuals with neurofibromatosis 1 develop cutaneous neurofibromas, benign nerve sheath tumors that manifest as nodules on the skin. These cutaneous neurofibromas emerge with age, appearing most commonly in adolescence. Nevertheless, few data have been published on how adolescents with neurofibromatosis 1 feel about cutaneous neurofibromas. The purpose of this study was to assess the perspectives of adolescents with neurofibromatosis 1 and their caregivers regarding cutaneous neurofibroma morbidity, treatment options, and acceptable risks-benefits of treatment., Methods: An online survey was distributed through the world's largest NF registry. Eligibility criteria included self-reported neurofibromatosis 1 diagnosis, adolescent child ages 12-17 years, ≥1 cutaneous neurofibroma, and ability to read English. The survey was designed to collect details about the adolescent's cutaneous neurofibromas, views on morbidity related to cutaneous neurofibromas, social and emotional impact of cutaneous neurofibromas, communication regarding cutaneous neurofibromas, and views regarding current and potential future cutaneous neurofibroma treatment., Results: Survey respondents included 28 adolescents and 32 caregivers. Adolescents reported having several negative feelings about cutaneous neurofibromas, particularly feeling worried about the potential progression of their cutaneous neurofibromas (50%). Pruritus (34%), location (34%), appearance (31%), and number (31%) were the most bothersome cutaneous neurofibroma features. Topical medication (77%-96%), followed by oral medication (54%-93%), was the most preferred treatment modality. Adolescents and caregivers most often replied that cutaneous neurofibroma treatment should be initiated when cutaneous neurofibromas become bothersome. The majority of respondents were willing to treat cutaneous neurofibromas for at least 1 year (64%-75%). Adolescent and caregivers were least willing to risk pain (72%-78%) and nausea/vomiting (59%-81%) as a cutaneous neurofibroma treatment side effect., Conclusions: These data indicate that adolescents with neurofibromatosis 1 are negatively impacted by their cutaneous neurofibromas, and that both adolescents and their caregivers would be willing to try longer-term experimental treatments., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K.Y.S. is on the scientific advisory board for NFlection Therapeutics. S.R.P. is co-founder of NFlection Therapeutics and NF2 Therapeutics; serves on the scientific advisory board of SonALAsense; and consults for Akouos. The other authors have no conflicts of interest to disclose.

Neurofibromatosis type 1 is a genetic syndrome characterized by a wide variety of tumor and non-tumor manifestations. Bone-related issues, such as scoliosis, tibial dysplasia, and low bone mineral density, are a significant source of morbidity for this population with limited treatment options. Some of the challenges to developing such treatments include the lack of consensus regarding the optimal methods to assess bone health in neurofibromatosis type 1 and limited data regarding the natural history of these manifestations. In this review, the Functional Committee of the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration: (1) presents the available techniques for measuring overall bone health and metabolism in persons with neurofibromatosis type 1, (2) reviews data for use of each of these measures in the neurofibromatosis type 1 population, and (3) describes the strengths and limitations for each method as they might be used in clinical trials targeting neurofibromatosis type 1 bone manifestations. The Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration supports the development of a prospective, longitudinal natural history study focusing on the bone-related manifestations and relevant biomarkers of neurofibromatosis type 1. In addition, we suggest that the neurofibromatosis type 1 research community consider adding the less burdensome measurements of bone health as exploratory endpoints in ongoing or planned clinical trials for other neurofibromatosis type 1 manifestations to expand knowledge in the field., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AMG and LJK have served as unpaid advisors for AstraZeneca/Alexion; AMG has been an unpaid advisor for SpringWorks Therapeutics. DAS has been a paid consultant for Alexion. HS is CEO of Infixion Bioscience, Inc., a pharmaceutical R&D company targeting NF1.

Pseudoprogression, defined as the radiographic false appearance of disease progression, is not frequently observed in patients with malignant peripheral nerve sheath tumor (MPNST). We report on a case of a patient with neurofibromatosis type 1 (NF1) MPNST pseudoprogression that presented as suspected local recurrence 9.5 years after last treatment. The patient underwent surgical resection following growth of a mass on sequential MRI imaging; surgical pathology, however, showed skeletal muscle with atrophy, fibroadipose tissue, and fat necrosis, without any evidence of tumor. As MPNST survival rates increase, physicians should consider pseudoprogression as a potential presentation after prior treatment., Competing Interests: Mr. Andrés Lessing has no conflicts of interest to declare. Dr. Thomas DeLaney has no conflicts of interest to declare. Dr. Gregory M. Cote reports Advisory Board fees from Agios, Epizyme, and PharmaMar; Support provided to his institution for the conduct of clinical trials from Agios, Epizyme, PharmaMar, Eisai, Macrogenics, Boston Biomedical, Plexxicon, Merck KGaA/EMD Serono Research and Development Institute, CBA, SpringWorks Therapeutics, Bavarian-Nordic, and Bayer. Dr. Kevin Raskin has no conflicts of interest to declare. Dr. Scott Plotkin reports co-founding NFlection Therapeutics and NF2 Therapeutics and consulting for AstraZeneca, Akouos, and SonALAsense. Dr. Juan Lessing has no conflicts of interest to declare., (Copyright © 2021 by S. Karger AG, Basel.)

Objective: To assess imaging utilization practices across clinical specialists in neurofibromatosis type 1 (NF1) for the evaluation of symptomatic and asymptomatic children and adults with or without plexiform neurofibromas (PN)., Methods: An institutional review board-exempt survey was administered to medical practitioners caring for individuals with NF1 at the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) meeting in September 2019. The survey included questions on respondent demographic data (9 questions), type of imaging obtained for asymptomatic (4 questions) and symptomatic (4 questions) people with and without PN, and utilization of diffusion-weighted imaging (2 questions)., Results: Thirty practitioners participated in the survey. Most were academic neuro-oncologists at high-volume (>10 patients/week) NF1 centers. Of 30 respondents, 26 had access to whole-body MRI (WB-MRI). The most common approach to an asymptomatic person without PN was no imaging (adults: 57% [17/30]; children: 50% [15/30]), followed by a screening WB-MRI (adults: 20% [6/30]; children: 26.7% [8/30]). The most common approach to a person with symptoms or known PN was regional MRI (adults: 90% [27/30]; children: 93% [28/30]), followed by WB-MRI (adults: 20% [6/30]; children: 36.7% [11/30]). WB-MRI was most often obtained to evaluate a symptomatic child with PN (37% [11/30])., Conclusions: More than 90% of practitioners indicated they would obtain a regional MRI in a symptomatic patient without known or visible PN. Otherwise, there was little consensus on imaging practices. Given the high prevalence of PN and risk of malignant conversion in this patient population, there is a need to define imaging-based guidelines for optimal clinical care and the design of future clinical trials., (© 2021 American Academy of Neurology.)

Objective: As part of an evaluation of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration patient representative program, we surveyed REiNS members to (1) identify facilitators and barriers to involving patient representatives and (2) understand whether and how involving patient representatives affected recommendations for clinical trial outcomes., Methods: We administered an anonymous online survey to all REiNS members. Facilitators and barriers to patient representative involvement were solicited using a modified free listing technique; responses were inductively grouped into higher-order categories and ranked based on saliency score (Smith s ). Open-ended questions assessed patient representative expectations for engagement, perceived benefits/costs of patient engagement, and patient representative contributions; responses were analyzed using conventional content analysis., Results: A total of 63/172 (37%) members responded, including 18/30 (60%) patient representatives. Providing sufficient opportunities to meaningfully engage in research tasks and cultivating a respectful, inclusive atmosphere were key facilitators to patient representatives' satisfaction and ability to make an impact. Respondents perceived that patient representatives directly (through their input on research tasks) and indirectly (through effects on other stakeholders' knowledge and communication style) improved the organization's research, leading to selection of more meaningful, relevant, and feasible clinical trial outcome measures. Ongoing challenges to patient engagement include difficulty scheduling meetings and concerns about the level of scientific knowledge patient representatives needed to effectively engage., Conclusions: Involving patient representatives in REiNS improved perceived quality of neurofibromatosis clinical trial outcome measures. Negotiating sufficient opportunities to engage, fostering an inclusive atmosphere, and navigating time pressures are key to effective patient engagement., (© 2021 American Academy of Neurology.)

Objective: To assess the perspectives of adults with neurofibromatosis 1 (NF1) regarding cutaneous neurofibroma (cNF) morbidity, treatment options, and acceptable risk-benefit ratio to facilitate the design of patient-centered clinical trials., Methods: An online survey developed by multidisciplinary experts and patient representatives of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) cNF Working Group was distributed to adults with NF1 (n = 3,734) in the largest international database of individuals with any form of NF. Eligibility criteria included self-reported NF1 diagnosis, age ≥18 years, ≥1 cNF, and ability to read English., Results: A total of 548 adults with NF1 responded to the survey. Respondents ranked appearance, number, and then location as the most bothersome features of raised cNF. Seventy-five percent of respondents considered a partial decrease of 33%-66% in the number or size of cNF as a meaningful response to experimental treatments. Most respondents (48%-58%) were willing to try available cNF treatments but were not aware of options outside of surgical removal. Regarding experimental agents, respondents favored topical, then oral medications. Most individuals (>65%) reported being "very much" or "extremely willing" to try experimental treatments, especially those with the highest cNF burden. Many respondents were not willing to tolerate side effects like nausea/vomiting (51%) and rash (46%). The greatest barriers to participation in cNF clinical trials were cost of participation and need to take time off work., Conclusions: Most adults with NF1 are willing to consider experimental therapies for treatment of cNF. These data will guide the design of patient-centered clinical trials for adults with cNF., (© 2021 American Academy of Neurology.)

Competing Interests: Competing interests: none.

Bacteria frequently encounter selection by both antibiotics and lytic bacteriophages. However, the evolutionary interactions between antibiotics and phages remain unclear, in particular, whether and when phages can drive evolutionary trade-offs with antibiotic resistance. Here, we describe Escherichia coli phage U136B, showing it relies on two host factors involved in different antibiotic resistance mechanisms: 1) the efflux pump protein TolC and 2) the structural barrier molecule lipopolysaccharide (LPS). Since TolC and LPS contribute to antibiotic resistance, phage U136B should select for their loss or modification, thereby driving a trade-off between phage resistance and either of the antibiotic resistance mechanisms. To test this hypothesis, we used fluctuation experiments and experimental evolution to obtain phage-resistant mutants. Using these mutants, we compared the accessibility of specific mutations (revealed in the fluctuation experiments) to their actual success during ecological competition and coevolution (revealed in the evolution experiments). Both tolC and LPS-related mutants arise readily during fluctuation assays, with tolC mutations becoming more common during the evolution experiments. In support of the trade-off hypothesis, phage resistance via tolC mutations occurs with a corresponding reduction in antibiotic resistance in many cases. However, contrary to the hypothesis, some phage resistance mutations pleiotropically confer increased antibiotic resistance. We discuss the molecular mechanisms underlying this surprising pleiotropic result, consideration for applied phage biology, and the importance of ecology in evolution of phage resistance. We envision that phages may be useful for the reversal of antibiotic resistance, but such applications will need to account for unexpected pleiotropy and evolutionary context., Competing Interests: Competing interest statement: P.E.T. discloses a financial interest in Felix Biotechnology Inc., a company that seeks to commercially develop phages for use as therapeutics, with certain rights to license any patents resulting from this work. A.R.B., B.K.C., and P.E.T. disclose a provisional patent application involving phage therapy., (Copyright © 2020 the Author(s). Published by PNAS.)

Objective: In autumn 2012, Massachusetts schools implemented comprehensive competitive food and beverage standards similar to the US Department of Agriculture's Smart Snacks in School standards. We explored major themes raised by food-service directors (FSD) regarding their school-district-wide implementation of the standards., Design: For this qualitative study, part of a larger mixed-methods study, compliance was measured via direct observation of foods and beverages during school site visits in spring 2013 and 2014, calculated to ascertain the percentage of compliant products available to students. Semi-structured interviews with school FSD conducted in each year were analysed for major implementation themes; those raised by more than two-thirds of participating school districts were explored in relationship to compliance., Setting: Massachusetts school districts (2013: n 26; 2014: n 21)., Subjects: Data collected from FSD., Results: Seven major themes were raised by more than two-thirds of participating school districts (range 69-100 %): taking measures for successful transition; communicating with vendors/manufacturers; using tools to identify compliant foods and beverages; receiving support from leadership; grappling with issues not covered by the law; anticipating changes in sales of competitive foods and beverages; and anticipating changes in sales of school meals. Each theme was mentioned by the majority of more-compliant school districts (65-81 %), with themes being raised more frequently after the second year of implementation (range increase 4-14 %)., Conclusions: FSD in more-compliant districts were more likely to talk about themes than those in less-compliant districts. Identified themes suggest best-practice recommendations likely useful for school districts implementing the final Smart Snacks in School standards, effective July 2016.

A pilot study was carried out to determine whether autotransfusion increased the platelet count. Although only a small series was involved significant increases were shown.

A continuous infusion technique for atracurium was investigated. It provided a stable neuromuscular block, with a mean infusion rate of 0.008 mg/kg/min after an initial bolus of 0.5 mg/kg. A wide individual response was found and an arbitrary infusion rate based on mass alone is therefore not possible. The above rate is thus a starting point and should be adjusted according to individual requirements, preferably by using a peripheral nerve stimulator. The technique obviates the need for repeated increments of atracurium during lengthy surgical procedures.

A technique for postoperative autotransfusion in open-heart surgery, involving minimal blood damage and contamination, is described.

Atracurium 0.3 mg/kg was compared with alcuronium 0.25 mg/kg as the sole muscle relaxant for tracheal intubation and abdominal relaxation for gynaecological laparoscopy in 46 patients during nitrous oxide, oxygen and halothane anaesthesia. Speed of onset, intubation conditions, effect on blood pressure and pulse rate, and ease of reversal were compared. Alcuronium had a significantly faster onset of action than atracurium; intubation conditions were adequate and abdominal relaxation was satisfactory for both drugs. The effect of atracurium was readily reversible within 10 minutes; in contrast alcuronium was significantly more resistant and mean recovery time was 28.03 minutes. Although alcuronium provided good muscle relaxation, it is not suitable for short procedures because of difficulty in reversing its action. Atracurium allowed earlier and more complete reversal of neuromuscular block.

A study was undertaken to determine whether a volume of oxygen injected from a 100 ml syringe and inhaled during a 10 m ascent would be exhaled again fully or partially by two experienced male divers. Each performed one apnoeic dive with and another without O2 augmentation. Analyses of mouth gas showed that the injected O2 had disappeared when the divers reached the surface. Any movement of the injected O2 to the alveoli through an open glottis probably resulted from simple diffusion as well as from agitation and mixing of gases by simulated respiratory activity. High-frequency positive-pressure ventilation applied by several authors, whereby sufficient gas exchange is achieved by oscillating small tidal volumes at frequencies of up to 900 per minute, may substantiate this possibility. The injected O2 was found also to have disappeared from the alveolar gas, shown by a comparison of O2 fraction differences between augmented and non-augmented dives. Injection and inhalation of the additional O2 will raise the partial pressure of O2 in the alveoli and increase oxygen transfer across the alveolar membrane into the blood, with more molecules being taken up within seconds during the ascent time. O2 augmentation in larger volumes during apnoeic diving could lead to a burst lung and must be regarded with suspicion. There is evidence that O2 augmentation by means of a small syringe attached to a trained diver's snorkel will help prevent apnoeic blackout.

The problem of tamponade due to rupture of an amoebic abscess, although rare, is extremely complex, and in the planning of the anaesthetic technique the following factors should receive attention: (i) the low cardiac output in which bradycardia, vasodilation, high inflation pressures and excessive fluid load must be avoided: (ii) pulmonary complications in which a double-lumen endotracheal tube should be considered; and (iii) sepsis.