Second Data Release from the European Pulsar Timing Array: Challenging the Ultralight Dark Matter Paradigm.

Pulsar Timing Array experiments probe the presence of possible scalar or pseudoscalar ultralight dark matter particles through decade-long timing of an ensemble of galactic millisecond radio pulsars. With the second data release of the European Pulsar Timing Array, we focus on the most robust scenario, in which dark matter interacts only gravitationally with ordinary baryonic matter. Our results show that ultralight particles with masses 10^{-24.0} eV≲m≲10^{-23.3} eV cannot constitute 100% of the measured local dark matter density, but can have at most local density ρ≲0.3 GeV/cm^{3}.

Significance of photodocumentation-associated factors in colonoscopy on the detection rate of colorectal neoplasms.

OBJECTIVE: It is unclear whether photodocumentation is associated with colorectal neoplasm (CRN) detection at colonoscopy, despite its ability to take more images with the development of affordable digital imaging systems. This study aimed to investigate whether photodocumentation-related factors could affect the detection rate of CRNs in healthy subjects. PATIENTS AND METHODS: A total of 2,637 subjects undergoing screening colonoscopy in routine health check-ups at CHA Bundang Medical from January to September 2016 were enrolled in this study. Only the endoscopic image data for observation purposes during colonoscopy withdrawal was used in this analysis. The number of observation images, observation time and the speed of photodocumentation (SPD) defined as the number of observation images per minute were used as quantity measures of photodocumentation. The presence of documented anatomical landmarks such as appendix orifice (AO), ileocecal valve (ICV), anorectal junction was used as quality measures of photodocumentation. RESULTS: Among subject-related factors, the independent factors for CRN detection in the multivariate analysis were age, male sex, waist circumference, and family history of colorectal cancer. In photo-documentation-related factors, SPD [Odds ratio (OR) 0.800; 95% confidence interval (CI), 0.740 to 0.864], observation time over 6 min (OR 1.671; 95% CI, 1.145 to 2.439), clear documentation of appendix orifice (AO) (OR 5.976; 95% CI, 4.548 to 7.852) and ileocecal valve (ICV) (OR 3.826; 95% CI, 2.985 to 4.904), and endoscopists (p < 0.001) were independently significant factors. However, the number of observation images was not associated with the detection of CRNs. CONCLUSIONS: Lower SPD and clear documentation of cecal landmarks might be associated with an increased detection rate of CRNs.

A fast radio burst source at a complex magnetized site in a barred galaxy.

Fast radio bursts (FRBs) are highly dispersed, millisecond-duration radio bursts1-3. Recent observations of a Galactic FRB4-8 suggest that at least some FRBs originate from magnetars, but the origin of cosmological FRBs is still not settled. Here we report the detection of 1,863 bursts in 82 h over 54 days from the repeating source FRB 20201124A (ref. 9). These observations show irregular short-time variation of the Faraday rotation measure (RM), which scrutinizes the density-weighted line-of-sight magnetic field strength, of individual bursts during the first 36 days, followed by a constant RM. We detected circular polarization in more than half of the burst sample, including one burst reaching a high fractional circular polarization of 75%. Oscillations in fractional linear and circular polarizations, as well as polarization angle as a function of wavelength, were detected. All of these features provide evidence for a complicated, dynamically evolving, magnetized immediate environment within about an astronomical unit (AU; Earth-Sun distance) of the source. Our optical observations of its Milky-Way-sized, metal-rich host galaxy10-12 show a barred spiral, with the FRB source residing in a low-stellar-density interarm region at an intermediate galactocentric distance. This environment is inconsistent with a young magnetar engine formed during an extreme explosion of a massive star that resulted in a long gamma-ray burst or superluminous supernova.

Organizing a Successful Practice and Considering Tax and Estate Planning.

To care for your family and to do "good" for your alma mater, religious organization, and the other charities you love, you need to do "well," which is to build a successful practice. To achieve a successful practice, following the principles of the dozen A's is helpful: Ability, Availability, Amicability, Approachable, Attuned, Aware, Attentive to patients, Attentive to others, Attentive to details, Apology (ability to apologize and accept apology gracefully), Assimilate, Affordable. Another way to put it is "skills to treat, heart to care at a sensible price."

Guiding Chemically Synthesized Peptide Drug Lead Optimization by Derisking Mast Cell Degranulation-Related Toxicities of a NaV1.7 Peptide Inhibitor.

Studies have shown that some peptides and small molecules can induce non IgE-mediated anaphylactoid reactions through mast cell activation. Upon activation, mast cells degranulate and release vasoactive and proinflammatory mediators, from cytoplasmic granules into the extracellular environment which can induce a cascade of severe adverse reactions. This study describes a lead optimization strategy to select NaV1.7 inhibitor peptides that minimize acute mast cell degranulation (MCD) toxicities. Various in vitro, in vivo, and PKPD models were used to screen candidates and guide peptide chemical modifications to mitigate this risk. Anesthetized rats dosed with peptides demonstrated treatment-related decreases in blood pressure and increases in plasma histamine concentrations which were reversible with a mast cell stabilizer, supporting the MCD mechanism. In vitro testing in rat mast cells with NaV1.7 peptides demonstrated a concentration-dependent increase in histamine. Pharmacodynamic modeling facilitated establishing an in vitro to in vivo correlation for histamine as a biomarker for blood pressure decline via the MCD mechanism. These models enabled assessment of structure-activity relationship (SAR) to identify substructures that contribute to peptide-mediated MCD. Peptides with hydrophobic and cationic characteristics were determined to have an elevated risk for MCD, which could be reduced or avoided by incorporating anionic residues into the protoxin II scaffold. Our analyses support that in vitro MCD assessment in combination with PKPD modeling can guide SAR to improve peptide lead optimization and ensure an acceptable early in vivo tolerability profile with reduced resources, cycle time, and animal use.

Micro-electromechanical-system-tuned resonant filters spanning the 8-12 µm band.

The spectral band covering ∼8-12µm is atmospherically transparent and therefore important for terrestrial imaging, day/night situational awareness systems, and spectroscopic applications. There is a dearth of tunable filters spanning the band. Here, we propose and demonstrate a new, to the best of our knowledge, tunable-filter method engaging the fundamental physics of the guided-mode resonance (GMR) effect realized with a non-periodic lattice. The polarization-dependent filter is fashioned with a one-dimensional Ge grating on a ZnSe substrate and interrogated with a ∼1.5mm Gaussian beam to show clear transmittance nulls. To expand the tuning range, the device parameters are optimized for sequential operation in TM and TE polarization states. The theoretical model exhibits a tunable range exceeding 4 µm, thus covering the band fully. In the experiment, a prototype device exhibits a spectral range of 8.6-10.0 µm in TM and 9.9-11.7 µm in TE polarization or >3µm total. With additional efforts in fabrication, we expect to achieve the full range.

No pulsed radio emission during a bursting phase of a Galactic magnetar.

Fast radio bursts (FRBs) are millisecond-duration radio transients of unknown physical origin observed at extragalactic distances1-3. It has long been speculated that magnetars are the engine powering repeating bursts from FRB sources4-13, but no convincing evidence has been collected so far14. Recently, the Galactic magnetar SRG 1935+2154 entered an active phase by emitting intense soft γ-ray bursts15. One FRB-like event with two peaks (FRB 200428) and a luminosity slightly lower than the faintest extragalactic FRBs was detected from the source, in association with a soft γ-ray/hard-X-ray flare18-21. Here we report an eight-hour targeted radio observational campaign comprising four sessions and assisted by multi-wavelength (optical and hard-X-ray) data. During the third session, 29 soft-γ-ray repeater (SGR) bursts were detected in γ-ray energies. Throughout the observing period, we detected no single dispersed pulsed emission coincident with the arrivals of SGR bursts, but unfortunately we were not observing when the FRB was detected. The non-detection places a fluence upper limit that is eight orders of magnitude lower than the fluence of FRB 200428. Our results suggest that FRB-SGR burst associations are rare. FRBs may be highly relativistic and geometrically beamed, or FRB-like events associated with SGR bursts may have narrow spectra and characteristic frequencies outside the observed band. It is also possible that the physical conditions required to achieve coherent radiation in SGR bursts are difficult to satisfy, and that only under extreme conditions could an FRB be associated with an SGR burst.

Diverse polarization angle swings from a repeating fast radio burst source.

Fast radio bursts (FRBs) are millisecond-duration radio transients1,2 of unknown origin. Two possible mechanisms that could generate extremely coherent emission from FRBs invoke neutron star magnetospheres3-5 or relativistic shocks far from the central energy source6-8. Detailed polarization observations may help us to understand the emission mechanism. However, the available FRB polarization data have been perplexing, because they show a host of polarimetric properties, including either a constant polarization angle during each burst for some repeaters9,10 or variable polarization angles in some other apparently one-off events11,12. Here we report observations of 15 bursts from FRB 180301 and find various polarization angle swings in seven of them. The diversity of the polarization angle features of these bursts is consistent with a magnetospheric origin of the radio emission, and disfavours the radiation models invoking relativistic shocks.

Role of a modified ultrafast MRI brain protocol in clinical paediatric neuroimaging.

AIM: To establish a role for modified ultrafast magnetic resonance imaging (MRI) of the brain in clinical paediatric patients based on clinically acceptable image quality and diagnostic accuracy. MATERIALS AND METHODS: A prospective study was conducted with institutional review board approval on an ultrafast MRI brain protocol consisting of sagittal T1-weighted, axial T2-weighted, axial fluid-attenuated inversion recovery (FLAIR), axial diffusion-weighted imaging (DWI), and axial T2∗-weighted sequences. Preliminary investigations revealed that the default ultrafast T2-weighted sequence was prone to pulsation artefacts. A modified ultrafast T2-weighted sequence was therefore developed to replace the default ultrafast T2-weighted sequence. Thirty-five patients with clinical indication for neuroimaging underwent ultrafast MRI, modified ultrafast T2-weighted sequence and standard MRI at 3 T. Image quality of ultrafast MRI sequences were graded as clinically "diagnostic" or "non-diagnostic" and compared against the corresponding standard MRI sequences as the reference standard. The modified ultrafast T2-weighted sequence surpassed the default ultrafast T2-weighted sequence in image quality. The ultrafast MRI protocol was therefore replaced with the modified ultrafast T2-weighted sequence creating a modified ultrafast MRI protocol. The clinical reports of modified ultrafast MRI were compared against standard MRI for diagnostic concordance, categorised further as "normal", "clinically significant", or "clinically minor" abnormalities. RESULTS: Ultrafast T1-weighted, FLAIR, and DWI sequences had comparable image quality to standard MRI sequences. The ultrafast T2∗-weighted sequence had significantly higher non-diagnostic images (42.9%) compared to the standard MRI sequence (2.9%). The default ultrafast T2-weighted sequence had significantly higher non-diagnostic images compared to the modified ultrafast T2-weighted sequence and standard T2-weighted sequence (82.9%, 5.7%, 8.6%, respectively). There was 100% concordance for normal and clinically significant abnormalities and 23% discordance for clinically minor abnormalities. Modified ultrafast MRI takes 5 minutes 41 seconds compared to standard MRI time of 14 minutes 57 seconds. CONCLUSION: The modified ultrafast MRI protocol for brain imaging demonstrates clinically acceptable image quality in four out of five sequences and has high accuracy in diagnosing normal and clinically significant abnormalities when compared against the standard MRI protocol for brain imaging. It could potentially benefit a select group of paediatric patients who require neuroimaging.

Unpolarized resonant notch filters for the 8-12 µm spectral region.

The long-wave infrared (LWIR) spectral region spanning ∼8-12µm is useful for many scientific and industrial applications. As traditional multilayer film components are not straightforwardly realized at these bands, we provide design, fabrication, and testing of polarization independent bandstop filters based on the guided-mode resonance (GMR) effect. Focusing on the zero-contrast grating architecture, we successfully fabricate prototype filters in the Ge-on-ZnSe materials system. Applying mask-based photolithography and dry etching, photoresist patterns form the desired Ge grating structures. The resulting devices exhibit clean transmittance nulls and acceptably high sidebands. Moreover, we verify polarization independent notch filtering by assembling two identical GMR filters with gratings oriented orthogonally. This approach to realize effective GMR elements will be useful for various fields including photonic and optoelectronic devices operating in the LWIR region.

Otolaryngologist as a Political Leader?

Otolaryngologists are in a good position to advocate for our patients and our specialty. We can do it as a volunteer or as a full-time job running for political office at the state or federal level. To be taken seriously, we need to offer solutions besides citing the problems. We encourage otolaryngologists to work with our Academy and its ENT-PAC (Ear, Nose, Throat Political Action Committee). Medicine is a great profession and Otolaryngology-Head and Neck Surgery is an even better specialty.

Prospective randomized comparison of cerebrospinal fluid aspiration and conventional popping methods using 27-gauge spinal needles in patients undergoing spinal anaesthesia.

BACKGROUND: Performing spinal anaesthesia using the conventional popping method with a 27-gauge (27G) spinal needle is technically difficult. In this study, we compared the aspiration and conventional popping method for spinal anaesthesia using 27G Quincke-type needles. METHODS: This prospective, randomized study enrolled 90 patients, aged 19 to 65 years, with American Society of Anesthesiologists physical status I-III, who were undergoing spinal anaesthesia. Patients were randomly assigned to one of two groups using a computer-generated random number table: patients receiving spinal anaesthesia using the aspiration method, in which the needle is advanced with continuous aspiration, or the conventional popping method. The primary outcome measure was the success rate of the first attempt to perform dural puncture. Number of attempts and passages, withdrawal cases, successful attempt time, total procedure time, and actual depth of dural puncture were recorded. RESULTS: Eighty-eight patients were included in the study. In the aspiration group, the success rate of first attempt for dural puncture was 93.3%, compared with 72.1% in the popping group (P = 0.019). Success involving needle withdrawal was recorded in 4 (8.9%) patients in the aspiration group and 13 (30.2%) in the popping group (P = 0.024). In the popping group, the number of attempts was significantly higher (P = 0.044), and total procedure time was significantly longer (P = 0.023). Actual depths of dural puncture were deeper in the popping group than in the aspiration group (P = 0.019). CONCLUSIONS: The aspiration method using a 27G Quincke-type needle offers clinical benefits for dural puncture compared with the conventional popping method for spinal anaesthesia. TRIAL REGISTRATION: Clinical research information service number: KCT0002815, registered 21/Apr/2018. Retrospectively registered.

The interplay of sun damage and genetic risk in Australian multiple and single primary melanoma cases and controls.

BACKGROUND: Skin phenotype, host genotype and ultraviolet (UV) damage play a role in the development of melanoma. OBJECTIVES: To ascertain whether the level of UV damage at the site of melanomas was associated with genetic polymorphisms. METHODS: Deep phenotyping was performed on 1244 individuals; 281 with multiple primary melanomas (MPMs), 304 with single primary melanoma (SPM) and 659 convenience controls. Genotype data was generated using the Illumina CoreExome microarray platform, assaying over 500 000 single-nucleotide polymorphisms. A subset of variants were combined to assess a polygenic risk score (PRS) for melanoma. RESULTS: Most MPM cases were diagnosed in patients aged > 40 years, in sites with visible chronic UV damage. Women and those diagnosed at age ≤ 40 years were less likely to have perilesional UV damage. Patients with MPM had higher frequencies of MITF E318K, MC1R R-alleles and the ASIP risk haplotype. Individuals who had melanoma in a visibly UV-damaged site were more likely to carry MC1R rs75570604 [odds ratio (OR) 2·5], 9q31.2 rs10816595 (OR 1·4) and MTAP rs869329 (OR 1·4). These same alleles were more common in patients with MPM who were diagnosed at age ≤ 40 years. The mean PRS was significantly higher in MPM than in SPM and controls. Naevus count was comparable in early-onset MPM cases and those diagnosed at age > 40 years. CONCLUSIONS: Our cohort demonstrated higher frequencies of previously reported alleles associated with melanoma. MPM melanomas more commonly occur in UV-damaged areas, and these individuals are more likely to carry MC1R red hair colour alleles. Awareness of the interplay of genetic vulnerability with UV damage can stratify risk and guide recommendations for melanoma screening. What's already known about this topic? Skin phenotype, host genotype and ultraviolet (UV) damage all play a role in melanoma development. One of the main risk factors is a personal history of melanoma; second and subsequent primary melanomas account for over 20% of all melanomas registered in Queensland. Multiple loci are associated with melanoma risk, including many low-penetrance loci, which may have a cumulatively significant risk. Population-wide screening programmes for melanoma are not yet economically viable. What does this study add? Patients diagnosed with melanoma at age ≤ 40 years were more likely than older patients to have melanomas in non-UV-damaged sites. Patients with multiple melanomas had higher frequencies of MITF E318K, MC1R R-alleles, and the ASIP extended risk haplotype than patients with single melanoma. CDKN2A, MC1R and MTAP variants were more frequent in patients who developed melanomas at a younger age, but also in those whose melanomas were all on visibly UV-damaged sites. What is the translational message? Incorporating these genetic findings into the known risk factors of skin phenotype and visible UV damage may allow for a more customized and economically feasible approach to early detection of melanoma, particularly in younger patients. Plain language summary available online.

High naevus count and MC1R red hair alleles contribute synergistically to increased melanoma risk.

BACKGROUND: A high total body naevus count is the highest risk factor for melanoma; the phenotype of red hair colour, freckling and pale skin that burns easily, produced by MC1R R alleles, also predisposes to melanoma. OBJECTIVES: To determine whether the known melanoma risk factors of high naevus count and red hair or MC1R R alleles act synergistically to increase melanoma risk. METHODS: The Brisbane Naevus Morphology Study involved 1267 participants from volunteers presenting at a melanoma unit, dermatology outpatient clinic, private dermatology clinics, the Brisbane Longitudinal Twin Study and the QSkin Study. We examined pigmentation characteristics, total body naevus ≥ 5 mm count, and MC1R, ASIP and CDKN2A genotype in participants with and without a personal history of melanoma, living in Queensland, Australia, which is an area of high ultraviolet radiation. RESULTS: Cases were older than controls (median 57 vs. 33 years). Compared with individuals with dark brown hair and zero to four naevi, individuals with red hair and ≥ 20 naevi had a melanoma odds ratio of 10·0 (95% confidence interval 4·2-24·3). Individuals with MC1R R/R genotype and ≥ 20 naevi (≥ 5 mm diameter) had a melanoma odds ratio of 25·1 (95% confidence interval 8·4-82·7) compared with wild-type (WT)/WT individuals with zero to four naevi. The highest risk group is Australian men with the MC1R R/R genotype and ≥ 20 moles, who have an absolute risk of melanoma to age 75 years of 23·3%, compared with 0·8% for men with the WT/WT genotype and zero to four naevi. CONCLUSIONS: Patients who live in areas of high ultraviolet radiation, and have many large naevi and the red hair colour phenotype, particularly those with the MC1R R/R genotype, have a high risk of melanoma above the threshold recommended for screening in other cancers. Therefore, they should undergo intensive physician-led surveillance. What's already known about this topic? A high number of acquired melanocytic naevi, the red hair phenotype and MC1R R alleles all independently increase melanoma risk. Women with atypical naevi have an increasing melanoma risk gradient from darker hair to lighter hair. Women with many naevi have an increasing melanoma risk gradient from those with no elements of the red hair phenotype, to those with freckles but not red hair, to those with red hair. What does this study add? In Queensland, Australia, people with ≥ 20 naevi (≥ 5 mm diameter) and MC1R R/R genotype have a 25-fold increased melanoma risk, relative to people with zero to four naevi and the MC1R WT/WT genotype. In Queensland, individuals with ≥ 20 naevi and the MC1R R/R genotype have an absolute melanoma risk to age 75 years of 23·3% for men and 19·3% for women. This effect is independent of CDKN2A genotype. Further research is required to determine the effect of areas of lower ultraviolet radiation, as this study took place in the Queensland, Australia, which is an area of high ultraviolet radiation. MC1R R/r genotype is associated with increased total body naevus count but this is not the case for R/R. What is the translational message? Patients with many large naevi and the red hair colour phenotype, particularly those with an MC1R R/R genotype, have an unusually high risk of melanoma. In a high ultraviolet environment, this risk exceeds the threshold recommended for screening in other cancers, and such individuals should undergo intensive, regular, physician-led surveillance. Patients with many large naevi but with non-red colour hair may benefit further from clinical MC1R genotyping.

TEK is a novel prognostic marker for clear cell renal cell carcinoma.

OBJECTIVE: Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. However, effective therapeutics for ccRCC are lacking. Novel biomarkers could provide critical information when determining prognoses for patients with ccRCC. In this study, we sought to determine if the expression of receptor tyrosine kinase (TEK) could be a potential novel prognostic biomarker for ccRCC. TEK, originally identified as an endothelial cell-specific receptor, plays an important role in the modulation of vasculogenesis and remodeling. Altered TEK expression has been observed in tumor tissues (e.g., oral squamous cell carcinomas, leukemia) and breast, gastric and thyroid cancers. However, the role of TEK in ccRCC remains unknown. PATIENTS AND METHODS: Differential TEK expression between non-metastatic (stage M0) and metastatic (stage M1) ccRCC patient cohorts was determined from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). Furthermore, TEK expression was assessed as a prognostic factor using the time-dependent area under the curve (AUC) of Uno's C-index, the AUC value of the receiver operating characteristics (ROC) at 5 years, Kaplan-Meier survival curves and multivariate analyses. RESULTS: A Kaplan-Meier curve analysis revealed that the downregulation of TEK expression was associated with a poor prognosis for patients with ccRCC with good discrimination (p<0.0001 and p=0.0044 for the TGCA and ICGC cohorts, respectively). Analyses of C-indices and receiver operating characteristic AUC values further support this discriminative ability. Moreover, multivariate analyses showed the prognostic significance of TEK expression levels (p<0.001). CONCLUSIONS: Although additional clinical investigations will be needed, our results suggest that TEK is a potential biomarker for ccRCC.