Transient gas-induced differential refractive index effects in as-drawn hollow core optical fibers.

When a hollow core fiber is drawn, the core and cladding holes within the internal cane geometry are pressurized with an inert gas to enable precise control over the internal microstructure of the fiber and counteract surface tension forces. Primarily by considering the temperature drop as the fiber passes through the furnace and the geometrical transformation of the internal microstructure from preform-to-fiber, we recently established that the gas pressure within the final 'as-drawn' fiber is substantially below atmospheric pressure. We have also established that slight changes in the gas refractive index within the core and surrounding cladding holes induced by changes in gas pressure are sufficient to significantly affect both the modality and loss of the fiber. Here we demonstrate, through both simulations and experimental measurements, that the combination of these effects leads to transient changes in the fiber's attenuation when the fibers are opened to atmosphere post-fabrication. It is important to account for this phenomenon for accurate fiber characterization, particularly when long lengths of fiber are drawn where it could take many weeks for every part of the internal microstructure to reach atmospheric pressure.

Three stage HCF fabrication technique for high yield, broadband UV-visible fibers.

Hollow-core optical fibers can offer broadband, single mode guidance in the UV-visible-NIR wavelength range, with the potential for low-loss, solarization-free operation, making them desirable and potentially disruptive for a wide range of applications. To achieve this requires the fabrication of fibers with <300nm anti-resonant membranes, which is technically challenging. Here we investigate the underlying fluid dynamics of the fiber fabrication process and demonstrate a new three-stage fabrication approach, capable of delivering long (∼350m) lengths of fiber with the desired thin-membranes.

Pencil Beam Scanning Proton Therapy for Pregnant Patients With Brain and Head and Neck Cancers.

PURPOSE: When radiation therapy is medically necessary for pregnant patients, photon-based treatments (XRT) have traditionally been used, whereas proton radiation therapy (PRT) is avoided due to concerns about neutron dose. This retrospective study analyzes pregnant patients treated with XRT and models the equivalent dose that would have been delivered to the fetus with proton radiation compared with XRT. The purpose of this work is to provide a comprehensive analysis of pencil beam scanning proton therapy (PBS-PRT) for pregnant patients and to evaluate whether PBS-PRT should be the new standard of practice for treating pregnant patients with brain and head and neck cancers. METHODS AND MATERIALS: PBS-PRT plans were made for seven pregnant patients who received XRT: four treated for brain tumors and three for head and neck tumors. Measurements were performed with the patient plans using an anthropomorphic phantom and Wendi-2 meter placed at the phantom's abdomen. Patient-specific measurements were used to determine the total fetal equivalent dose from PBS-PRT compared with XRT. Imaging dose was also evaluated with a Fluke 451 dose meter. RESULTS: The average measured fetal equivalent dose, accounting for photons and neutrons, for the brain plans was 0.4 mSv for PBS-PRT and 7 mSv for XRT. For the head and neck plans, it was 6 mSv and 90 mSv for PBS-PRT and XRT, respectively. The PBS-PRT plans were preferred by the physicians for both tumor coverage and normal-tissue sparing. Daily imaging added between 0.05 and 1.5 mSv to the total dose. CONCLUSIONS: This retrospective study showed that when treating brain or head and neck cancers in pregnant patients, fetal equivalent dose is reduced by approximately a factor of 10 with PBS-PRT compared with XRT without making any compromises in treatment planning objectives. These results support a change of practice to using PBS-PRT as the new standard for treating pregnant patients with brain or head and neck tumors compared with XRT.

Near-infrared radiation induced attenuation in nested anti-resonant nodeless fibers.

This Letter reports the first, to the best of our knowledge, spectral radiation induced attenuation (RIA) measurements of nested anti-resonant nodeless hollow-core fibers (NANFs). A 5-tube NANF, alongside a solid-core single-mode radiation resistant fiber (SM-RRF), was irradiated under γ-ray up to 101 kGy (SiO2) and under x-ray up to 241 kGy (SiO2). No RIA was observed in the NANF in the second half of the O-band, the S-band, the C-band, and the L-band. The NANF showed a reduction of absorption bands associated with water and HCl under irradiation. Three new attenuation peaks were radiolytically induced and are attributed to the creation of HNO3. These peaks are centered respectively at 1441 nm, 1532 nm, and 1628 nm, with a full width at half maximum (FWHM) of, respectively, 10 nm, 12 nm, and 12 nm. These results demonstrate that the wide bandwidth range of NANFs is essentially unaffected by radiation, but the internal gas contents of the NANF must be managed to avoid producing undesirable spectral features through radiolytic reactions. Wide spectral regions almost unaffected by the ionizing radiation could open new possibilities for the use of NANF in harsh radiation environments.

Molecular landscape and functional characterization of centrosome amplification in ovarian cancer.

High-grade serous ovarian carcinoma (HGSOC) is characterised by poor outcome and extreme chromosome instability (CIN). Therapies targeting centrosome amplification (CA), a key mediator of chromosome missegregation, may have significant clinical utility in HGSOC. However, the prevalence of CA in HGSOC, its relationship to genomic biomarkers of CIN and its potential impact on therapeutic response have not been defined. Using high-throughput multi-regional microscopy on 287 clinical HGSOC tissues and 73 cell lines models, here we show that CA through centriole overduplication is a highly recurrent and heterogeneous feature of HGSOC and strongly associated with CIN and genome subclonality. Cell-based studies showed that high-prevalence CA is phenocopied in ovarian cancer cell lines, and that high CA is associated with increased multi-treatment resistance; most notably to paclitaxel, the commonest treatment used in HGSOC. CA in HGSOC may therefore present a potential driver of tumour evolution and a powerful biomarker for response to standard-of-care treatment.

The copy number and mutational landscape of recurrent ovarian high-grade serous carcinoma.

The drivers of recurrence and resistance in ovarian high grade serous carcinoma remain unclear. We investigate the acquisition of resistance by collecting tumour biopsies from a cohort of 276 women with relapsed ovarian high grade serous carcinoma in the BriTROC-1 study. Panel sequencing shows close concordance between diagnosis and relapse, with only four discordant cases. There is also very strong concordance in copy number between diagnosis and relapse, with no significant difference in purity, ploidy or focal somatic copy number alterations, even when stratified by platinum sensitivity or prior chemotherapy lines. Copy number signatures are strongly correlated with immune cell infiltration, whilst diagnosis samples from patients with primary platinum resistance have increased rates of CCNE1 and KRAS amplification and copy number signature 1 exposure. Our data show that the ovarian high grade serous carcinoma genome is remarkably stable between diagnosis and relapse and acquired chemotherapy resistance does not select for common copy number drivers.

Phase I randomized, observer-blinded, placebo-controlled study of a SARS-CoV-2 mRNA vaccine PTX-COVID19-B.

Access to vaccines against SARS-CoV-2 virus was limited in poor countries during the COVID-19 pandemic. Therefore, a low-cost mRNA vaccine, PTX-COVID19-B, was produced and evaluated in a Phase 1 trial. PTX-COVID19-B encodes Spike protein D614G variant without the proline-proline (986-987) mutation present in other COVID-19 vaccines. The aim of the study was to evaluate safety, tolerability, and immunogenicity of PTX-COVID19-B vaccine in healthy seronegative adults 18-64 years old. The trial design was observer-blinded, randomized, placebo-controlled, and tested ascending doses of 16-µg, 40-µg, or 100-µg in a total of 60 subjects who received two intramuscular doses, 4 weeks apart. Participants were monitored for solicited and unsolicited adverse events after vaccination and were provided with a Diary Card and thermometer to report any reactogenicity during the trial. Blood samples were collected on baseline, days 8, 28, 42, 90, and 180 for serum analysis of total IgG anti-receptor binding domain (RBD)/Spike titers by ELISA, and neutralizing antibody titers by pseudovirus assay. Titers in BAU/mL were reported as geometric mean and 95% CI per cohort. After vaccination, few solicited adverse events were observed and were mild to moderate and self-resolved within 48 h. The most common solicited local and systemic adverse event was pain at the injection site, and headache, respectively. Seroconversion was observed in all vaccinated participants, who showed high antibody titers against RBD, Spike, and neutralizing activity against the Wuhan strain. Neutralizing antibody titers were also detected against Alpha, Beta, and Delta variants of concerns in a dose dependent manner. All tested doses of PTX-COVID19-B were safe, well-tolerated, and provided a strong immunogenicity response. The 40-µg dose showed fewer adverse reactions than the 100-µg dose, and therefore was selected for a Phase 2 trial, which is currently ongoing.Clinical Trial Registration number: NCT04765436 (21/02/2021). ( https://clinicaltrials.gov/ct2/show/NCT04765436 ).

Proton Whole-Lung Irradiation: Initial Report of Outcomes.

PURPOSE: Whole-lung irradiation is typically used in pediatric patients to decrease the risk of future lung metastases, but radiation dose to normal tissue is associated with long-term risks. Proton whole-lung irradiation (PWLI) provides an opportunity to decrease radiation dose to normal tissue and potentially decrease late toxicity. METHODS AND MATERIALS: This retrospective study included patients treated with spot-scanning PWLI at a single institution. Toxicity and oncologic outcomes were reviewed. Intensity modulated radiation therapy (IMRT) plans were created prospectively or retrospectively for dosimetric comparisons. Simple paired t tests were performed to assess differences between IMRT and PWLI dosimetric parameters. RESULTS: Twelve patients treated with PWLI were included in this study. Median age was 15 years (range, 3-34). Most (75%) had Ewing sarcoma. Most (92%) received 15 Gy in 10 fractions PWLI, and 3 (25%) received a focal pulmonary boost. Median follow-up was 16.5 months (range, 0-40.4 months). At last follow-up, 1 patient died of disease, while 11 were still alive (7 without disease, 4 with ongoing disease). During and immediately after treatment, 5 patients developed fatigue, 2 patients developed cough, and 1 patient developed nausea. Each treatment-related adverse event was Common Terminology Criteria for Adverse Events (version 5.0) grade 1 and resolved within 3 weeks of treatment completion. No patients have experienced clinical or radiographic pneumonitis or evidence of clinically apparent cardiac toxicity. Compared with IMRT plans, PWLI decreased mean dose to the heart, coronary artery, cardiac valve, left ventricle, aorta, breast, esophagus, kidney, liver, pancreas, thyroid, stomach, and spleen (all P < .001), without sacrificing target coverage. CONCLUSIONS: PWLI is feasible to deliver, decreases dose to normal tissue compared with IMRT, and appears to be well-tolerated. PWLI provides potential for decreased late toxicity and merits further investigation.

Optical time domain backscattering of antiresonant hollow core fibers.

Today's lowest-loss hollow core fibers are based on antiresonance guidance. They have been shown both theoretically and experimentally to have very low levels of backscattering arising from the fiber structure - 45 dB below that of traditional optical fibers with a solid silica glass core. This makes their longitudinal characterization using conventional reflectometric techniques very challenging. However, it was recently estimated that when filled with air, their backscattering coefficient increases to about 30 dB below that of standard solid core fibers. This level should be measurable with commercially available high performance optical time domain reflectometers (OTDR). Here we demonstrate - for the first time to the best of our knowledge - the measurement of backscattering from the air inside a hollow core fiber. We show that the characterization of multi-km long hollow core fibers with 15 m spatial resolution is possible using a commercial OTDR instrument. To benefit from its full dynamic range, we strongly suppress the 4% back-reflections that ordinarily occur at the OTDR's standard fiber output when directly-connected to a hollow core fiber. Furthermore, low coupling loss into the hollow core fiber (0.3 dB in our experiment) also helps to maximize the achievable OTDR signal-to-noise ratio. This approach enables distributed characterization and fault-finding in low-loss hollow core fibers, a topic of increasing importance as these fibers are now starting to be installed in commercial optical communication networks.

Low loss and broadband low back-reflection interconnection between a hollow-core and standard single-mode fiber.

We report simultaneous low coupling loss (below 0.2 dB at 1550 nm) and low back-reflection (below -60 dB in the 1200-1600 nm range) between a hollow core fiber and standard single mode optical fiber obtained through the combination of an angled interface and an anti-reflective coating. We perform experimental optimization of the interface angle to achieve the best combination of performance in terms of the coupling loss and back-reflection suppression. Furthermore, we examine parasitic cross-coupling to the higher-order modes and show that it does not degrade compared to the case of a flat interface, keeping it below -30 dB and below -20 dB for LP11 and LP02 modes, respectively.

Hyperactivation of the proteasome in Caenorhabditis elegans protects against proteotoxic stress and extends lifespan.

Virtually all age-related neurodegenerative diseases (NDs) can be characterized by the accumulation of proteins inside and outside the cell that are thought to significantly contribute to disease pathogenesis. One of the cell's primary systems for the degradation of misfolded/damaged proteins is the ubiquitin proteasome system (UPS), and its impairment is implicated in essentially all NDs. Thus, upregulating this system to combat NDs has garnered a great deal of interest in recent years. Various animal models have focused on stimulating 26S activity and increasing 20S proteasome levels, but thus far, none have targeted intrinsic activation of the 20S proteasome itself. Therefore, we constructed an animal model that endogenously expresses a hyperactive, open gate proteasome in Caenorhabditis elegans. The gate-destabilizing mutation that we introduced into the nematode germline yielded a viable nematode population with enhanced proteasomal activity, including peptide, unstructured protein, and ubiquitin-dependent degradation activities. We determined these nematodes showed a significantly increased lifespan and substantial resistance to oxidative and proteotoxic stress but a significant decrease in fecundity. Our results show that introducing a constitutively active proteasome into a multicellular organism is feasible and suggests targeting the proteasome gating mechanism as a valid approach for future age-related disease research efforts in mammals.

High-energy, mid-IR, picosecond fiber-feedback optical parametric oscillator.

A compact, mid-infrared (MIR), synchronously pumped, fiber-feedback optical parametric oscillator (OPO) based on periodically poled lithium niobate (PPLN) is developed with tunable signal and idler wavelength ranges of 1472.0-1758.2 nm and 2559.1-3562.7 nm, respectively. A solid-core SMF-28 fiber and a hollow-core fiber (HCF) were used as the feedback fibers in order to compare the effect of their substantially different levels of nonlinearity. The OPO generates 1-MHz, 120-ps, MIR pulses with up to 1.50-µJ pulse energy and 11.7-kW peak power.

The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma.

PURPOSE: Ovarian high-grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of evolutionary advantage compared with early-stage tumors. EXPERIMENTAL DESIGN: We performed targeted next-generation sequencing and shallow whole-genome sequencing (sWGS) on pretreatment samples from 43 patients with FIGO stage I-IIA HGSC to investigate somatic mutations and copy-number (CN) alterations (SCNA). We compared results to pretreatment samples from 52 patients with stage IIIC/IV HGSC from the BriTROC-1 study. RESULTS: Age of diagnosis did not differ between early-stage and late-stage patients (median 61.3 years vs. 62.3 years, respectively). TP53 mutations were near-universal in both cohorts (89% early-stage, 100% late-stage), and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2. We also did not observe cohort-specific focal SCNA that could explain biological behavior. However, ploidy was higher in late-stage (median, 3.0) than early-stage (median, 1.9) samples. CN signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clusters that were prognostic. CONCLUSIONS: Early-stage and late-stage HGSCs have highly similar patterns of mutation and focal SCNA. However, CN signature analysis showed that late-stage disease has distinct signature exposures consistent with whole-genome duplication. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early-stage and late-stage or simply time-related markers of evolutionary fitness. See related commentary by Yang et al., p. 2730.

Mid-infrared silicon-on-insulator waveguides with single-mode propagation over an octave of frequency.

Increasing the working optical bandwidth of a photonic circuit is important for many applications, in particular chemical sensing at mid-infrared wavelengths. This useful bandwidth is not only limited by the transparency range of waveguide materials, but also the range over which a waveguide is single or multimoded for predictable circuit behaviour. In this work, we show the first experimental demonstration of "endlessly single-mode" waveguiding in silicon photonics. Silicon-on-insulator waveguides were designed, fabricated and characterised at 1.95 µm and 3.80 µm. The waveguides were shown to support low-loss propagation (1.46 ± 0.13 dB/cm loss at 1.95 µm and 1.55 ± 0.35 dB/cm at 3.80 µm) and single-mode propagation was confirmed at 1.95 µm, meaning that only the fundamental mode was present over the wavelength range 1.95 - 3.80 µm. We also present the prospects for the use of these waveguides in sensing applications.

The shared uncertainty experience of older adults with advanced cancer and their caregivers.

OBJECTIVE: One primary source of psychological distress in patients with cancer and their caregivers is uncertainty. However, the uncertainty trajectory and its relationship between older adults with advanced cancer and their caregivers have rarely been examined. This study describes the uncertainty trajectory in patient-caregiver dyads, explores the effect of geriatric assessment (GA) intervention on trajectory, and examines the interdependent relationship of uncertainty. METHODS: This secondary analysis used longitudinal data from a national cluster-randomized controlled trial examining a GA intervention compared to usual care. Participants completed the modified 9-item Mishel Uncertainty in Illness Scale at enrollment, 4-6 weeks, 3 months, and 6 months. The dyadic growth model and cross-lagged actor-partner interdependence model were used. RESULTS: A total of 397 dyads (patient age M = 76.81 ± SD5.43; caregiver age M = 66.69 ± SD12.52) were included. Both had a trend of decreased uncertainty over time (b = -0.16, p < 0.01). There was a greater decrease in uncertainty among caregivers in the GA group than those in the usual care group (b = -0.46, p = 0.02). For both patients and caregivers, their past uncertainty was a significant predictor of their own current uncertainty (i.e., actor effect, p < 0.01). The individual's past uncertainty was a significant predictor of the other dyad member's current uncertainty (i.e., partner effect, p < 0.05), indicating an interdependent relationship between patient and caregiver uncertainty over time. CONCLUSIONS: Findings suggest patient and caregiver function as a unit with uncertainty levels affecting each other. Future interventions could build on GA to address uncertainty for older patients with advanced cancer and caregivers.

Completion of Patient-Reported Outcome Questionnaires Among Older Adults with Advanced Cancer.

CONTEXT: Systematic collection of patient-reported outcomes (PROs) reduces symptom burden and improves quality of life. The ability of older adults to complete PROs, however, has not been thoroughly studied. OBJECTIVES: To determine whether older adults with advanced cancer received assistance completing PROs, the nature of the assistance, the factors associated with receiving assistance, and how the prevalence of assistance changed over time. METHODS: Data were obtained from a multisite cluster randomized controlled study of geriatric assessment (Clinicaltrials.gov: NCT02107443). Adults ≥70 years with advanced cancer completed multiple PROs at 4 time points (enrollment, 6 weeks, 3 months, 6 months). Factors associated with receipt of assistance were assessed with bivariate and multivariate analyses. RESULTS: The study included 541 adults (range 70-96 years, 49% female, mixed incurable cancer diagnoses). Twenty-eight percent (153/541) received assistance completing PROs. Of these, 42% received assistance from caregivers, 37% from research staff, and 15% from both. Factors associated with receiving assistance included older age [Adjusted Odds Ratio (AOR) 3.71, 95% Confidence Interval (CI) 1.03-13.38], lower education level (3.92, 2.11-7.29), impaired cognition (1.90, 1.23-2.93), impaired functional status (2.16, 1.33-3.52), and impaired hearing (1.38, 1.05-1.80). Eighty percent of individuals who received assistance were identified at study initiation. Receiving assistance decreased over time from 28% to 18%, partially due to drop-outs. CONCLUSION: Over a quarter of older adults with advanced cancer in this study received assistance completing PROs. Completing PROs is a key aspect of many clinical programs and cancer trials; assistance in completing PROs should be offered and provided.

Low loss and high performance interconnection between standard single-mode fiber and antiresonant hollow-core fiber.

We demonstrate halving the record-low loss of interconnection between a nested antiresonant nodeless type hollow-core fiber (NANF) and standard single-mode fiber (SMF). The achieved interconnection loss of 0.15 dB is only 0.07 dB above the theoretically-expected minimum loss. We also optimized the interconnection in terms of unwanted cross-coupling into the higher-order modes of the NANF. We achieved cross-coupling as low as -35 dB into the LP[Formula: see text] mode (the lowest-loss higher-order mode and thus the most important to eliminate). With the help of simulations, we show that the measured LP[Formula: see text] mode coupling is most likely limited by the slightly imperfect symmetry of the manufactured NANF. The coupling cross-talk into the highly-lossy LP[Formula: see text] mode ([Formula: see text] dB/km in our fiber) was measured to be below -22 dB. Furthermore, we show experimentally that the anti-reflective coating applied to the interconnect interface reduces the insertion loss by 0.15 dB while simultaneously reducing the back-reflection below -40 dB over a 60 nm bandwidth. Finally, we also demonstrated an alternative mode-field adapter to adapt the mode-field size between SMF and NANF, based on thermally-expanded core fibers. This approach enabled us to achieve an interconnection loss of 0.21 dB and cross-coupling of -35 dB into the LP[Formula: see text] mode.

Endogenous membrane stress induces T6SS activity in Pseudomonas aeruginosa.

The type 6 secretion system (T6SS) is a dynamic organelle encoded by many gram-negative bacteria that can be used to kill competing bacterial prey species in densely occupied niches. Some predatory species, such as Vibrio cholerae, use their T6SS in an untargeted fashion while in contrast, Pseudomonas aeruginosa assembles and fires its T6SS apparatus only after detecting initial attacks by other bacterial prey cells; this targeted attack strategy has been termed the T6SS tit-for-tat response. Molecules that interact with the P. aeruginosa outer membrane such as polymyxin B can also trigger assembly of T6SS organelles via a signal transduction pathway that involves protein phosphorylation. Recent work suggests that a phospholipase T6SS effector (TseL) of V. cholerae can induce T6SS dynamic activity in P. aeruginosa when delivered to or expressed in the periplasmic space of this organism. Here, we report that inhibiting expression of essential genes involved in outer membrane biogenesis can also trigger T6SS activation in P. aeruginosa Specifically, we developed a CRISPR interference (CRISPRi) system to knock down expression of bamA, tolB, and lptD and found that these knockdowns activated T6SS activity. This increase in T6SS activity was dependent on the same signal transduction pathway that was previously shown to be required for the tit-for-tat response. We conclude that outer membrane perturbation can be sensed by P. aeruginosa to activate the T6SS even when the disruption is generated by aberrant cell envelope biogenesis.