[18F]Difluorocarbene for positron emission tomography.

The advent of total-body positron emission tomography (PET) has vastly broadened the range of research and clinical applications of this powerful molecular imaging technology1. Such possibilities have accelerated progress in fluorine-18 (18F) radiochemistry with numerous methods available to 18F-label (hetero)arenes and alkanes2. However, access to 18F-difluoromethylated molecules in high molar activity is mostly an unsolved problem, despite the indispensability of the difluoromethyl group for pharmaceutical drug discovery3. Here we report a general solution by introducing carbene chemistry to the field of nuclear imaging with a [18F]difluorocarbene reagent capable of a myriad of 18F-difluoromethylation processes. In contrast to the tens of known difluorocarbene reagents, this 18F-reagent is carefully designed for facile accessibility, high molar activity and versatility. The issue of molar activity is solved using an assay examining the likelihood of isotopic dilution on variation of the electronics of the difluorocarbene precursor. Versatility is demonstrated with multiple [18F]difluorocarbene-based reactions including O-H, S-H and N-H insertions, and cross-couplings that harness the reactivity of ubiquitous functional groups such as (thio)phenols, N-heteroarenes and aryl boronic acids that are easy to install. The impact is illustrated with the labelling of highly complex and functionalized biologically relevant molecules and radiotracers.

Photoredox Nucleophilic (Radio)fluorination of Alkoxyamines.

Herein, we report a photoredox nucleophilic (radio)fluorination using TEMPO-derived alkoxyamines, a class of substrates accessible in a single step from a diversity of readily available carboxylic acids, halides, alkenes, alcohols, aldehydes, boron reagents, and C-H bonds. This mild and versatile one-electron pathway affords radiolabeled aliphatic fluorides that are typically inaccessible applying conventional nucleophilic substitution technologies due to insufficient reactivity and competitive elimination. Automation of this photoredox process is also demonstrated with a user-friendly and commercially available photoredox flow reactor and radiosynthetic platform, therefore expediting access to labeled aliphatic fluorides in high molar activity (Am) for (pre)clinical evaluation.

Comparisons of Communication in Medical Face-To-Face and Teleconsultations: A Systematic Review and Narrative Synthesis.

The COVID-19 pandemic has brought telemedicine into mainstream medical practice (although questions remain over its role in a post-pandemic world). Research suggests that most patients and providers are satisfied with the flexibility and convenience of teleconsultations. However, there is continuing uncertainty about whether this shift has a clinically relevant impact on the quality of doctor-patient interaction. We conducted a systematic search of studies comparing communication in medical face-to-face consultations and teleconsultations. We included only studies which examined communication directly using recordings, excluding studies which used questionnaires or interviews. Studies were appraised using modified versions of the Critical Appraisal Skills Programme (CASP) checklists. Our search yielded 25,348 records, of which 22 were included in the final review. These studies were conducted in various medical specialties. Methodologies included approaches based on quantified communication behaviors using coding systems and qualitative studies using microanalytic methods. Except for duration (where there was evidence of face-to-face consultations being longer), no differences between the two modes of communication were consistently identified. In the aggregate, however, statistically significant differences were more prominent in primary care and more likely to favor face-to-face consultations. Qualitative studies also highlighted differences in how communication behaviors were manifested in each modality. Because much of the examined research was conducted in selected or non-routine settings, its applicability to the less selective use of telemedicine during and after the pandemic is limited.

The 18F-Difluoromethyl Group: Challenges, Impact and Outlook.

The difluoromethyl functionality has proven useful in drug discovery, as it can modulate the properties of bioactive molecules. For PET imaging, this structural motif has been largely underexploited in (pre)clinical radiotracers due to a lack of user-friendly radiosynthetic routes. This Minireview provides an overview of the challenges facing radiochemists and summarises the efforts made to date to access 18F-difluoromethyl-containing radiotracers. Two distinct approaches have prevailed, the first of which relies on 18F-fluorination. A second approach consists of a 18F-difluoromethylation process, which uses 18F-labelled reagents capable of releasing key reactive intermediates such as the [18F]CF2H radical or [18F]difluorocarbene. Finally, we provide an outlook for future directions in the radiosynthesis of [18F]CF2H compounds and their application in tracer radiosynthesis.

Expedient Access to 18F-Fluoroheteroarenes via Deaminative Radiofluorination of Aniline-Derived Pyridinium Salts.

Herein, we disclose that pyridinium salts derived from abundant (hetero)anilines represent a novel precursor class for nucleophilic aromatic substitution reactions with [18F]fluoride. The value of this new 18F-fluorodeamination is demonstrated with the synthesis of over 30 structurally diverse and complex heteroaryl 18F-fluorides, several derived from scaffolds that were yet to be labelled with fluorine-18. The protocol tolerates heteroarenes and functionalities commonly found in drug discovery libraries, and is amenable to scale-up and automation on a commercial radiosynthesiser.

Comparing Companion Involvement in Clinical Telephone and Face-To-Face Consultations About Seizures.

Companions (i.e., friends, family members, and other accompanying persons) play an important role in seizure clinic consultations, providing information that patients cannot. The COVID-19 pandemic has seen an increase in these consultations being conducted via telephone. Little is known, however, about how this shift might affect companion participation. Using conversation analysis applied to a set of recorded telephone neurologist-patient-companion consultations (n = 9) and comparable moments drawn from a set of face-to-face consultations (n = 37) (both collected in the UK), we aimed to explore this impact and to identify communication methods that clinicians can use to manage companion participation during telephone consultations. We identified four ways in which participation was observably affected by the telephone. Telephone consultations could make it unclear whether a companion was present and make it difficult for the companion to communicate directly with the neurologist. Passing the floor from one speaker to another was more complex remotely, which could also restrict the patient's own participation once the companion had the floor. These issues are rooted in the limitations of the telephone as a communication medium. Based on the issues identified, we conclude our analysis by highlighting some of the ways in which neurologists and other health professionals can manage companion participation in telephone consultations. These include encouraging the use of speakerphone, checking whether a companion is present throughout the call, keeping track of who can hear what throughout the call, and directing questions using given names to avoid ambiguity.

Use of the Patient Health Questionnaire (PHQ-9) in Practice: Interactions between patients and physicians.

We analyze the use of nine-item Patient Health Questionnaire (PHQ-9), an instrument that is widely used in diagnosing and determining the severity of depression. Using conversation analysis, we show how the doctor deploys the PHQ-9 in response to the patient's doubts about whether she is depressed. Rather than relaying the PHQ-9 verbatim, the doctor deviates from the wording so that the response options are selectively offered to upgrade the severity of the patient's symptoms. This works in favor of a positive diagnosis and is used to justify a treatment recommendation that the patient previously resisted. This contrasted with the rest of the data set, where diagnosis was either not delivered (as patients are presenting with ongoing problems) or delivered without using the PHQ-9. When clinician-administered, the PHQ-9 can be influenced by how response items are presented. This can lead to either downgrading or upgrading the severity of depression.

Panoramic single-aperture multi-sensor light field camera.

We describe a panoramic camera using one monocentric lens and an array of light field (LF) sensors to capture overlapping contiguous regions of the spherical image surface. Refractive sub-field consolidators divide the light before the image surface and concentrate the sub-images onto the optically active areas of adjacent CMOS sensors. We show the design of a 160° × 24° field-of-view (FOV) LF camera, and experimental test of a three sensor F/2.5 96° × 24° and five sensor (25 MPixel) F/4 140° × 24° camera. We demonstrate computational field curvature correction, refocusing, resolution enhancement, and depth mapping of a laboratory scene. We also present a 155° full circular field camera design compatible with LF or direct 164 MPixel sensing of 13 spherical sub-images, fitting within a one inch diameter sphere.

Aryl Sulfonium Salts for Site-Selective Late-Stage Trifluoromethylation.

Incorporation of the CF3 group into arenes has found increasing importance in drug discovery. Herein, we report the first photoredox-catalyzed cross-coupling of aryl thianthrenium salts with a copper-based trifluoromethyl reagent, which enables a site-selective late-stage trifluoromethylation of arenes. The reaction proceeds with broad functional group tolerance, even for complex small molecules on gram scale. The method was further extended to produce pentafluoroethylated derivatives.

Improving clinical outcomes for women with overactive bladder or urinary retention symptoms: a comparison of motor response voltages (1-9 V) during Stage 1 sacral neuromodulation.

OBJECTIVE: To assess whether the utilisation of a motor response of <3 V during Stage 1 sacral neuromodulation (SNM) results in better clinical outcomes compared to >4 V in patients with overactive bladder (OAB) or urinary retention symptoms. PATIENTS AND METHODS: An observational, retrospective, double cohort review was conducted of 339 female patients who had experienced medically recalcitrant OAB or urinary retention symptoms. Between September 2001 and September 2014, both cohorts underwent successful Stage 1 to Stage 2 SNM placement. Group A, included 174 women with a motor response at ≤3 V; and Group B, evaluated 110 women with a motor response at ≥4 V for medically recalcitrant OAB. Group C, compared 33 women with a motor response at ≤3 V; and Group D, documented 22 women with a motor response at ≥4 V for non-obstructive urinary retention. Patients completed 3-day voiding diaries, the Urogenital Distress Inventory-6 (UDI-6), Incontinence Impact Questionnaire-7 (IIQ-7), and Patient Global Impression of Improvement Questionnaire. RESULTS: The mean (sd) follow-up was 116.3 (30.3) months in Group A and 112 (34.6) months in Group B (P < 0.354); 150.5 (20.4) months in Group C and 145.8 (17.2) months in Group D (P < 0.38). Successful conversion of Stage 1 to Stage 2 showed statistically significant improvement for both <3-V groups (Groups A and C). Group A had a 93.5% (174/186) conversion rate vs 72.3% (110/152) in Group B for OAB symptoms (P < 0.001). Group C had a 94% (34/36) conversion rate vs 70% (21/30) in Group D (P < 0.017). Defined as a ≥50% reduction in frequency, urgency, urgency incontinence and nocturia, and UDI-6 and IIQ-7 scores, the success rate for Group A was 82.1% (143/174) and for Group B was 63% (69/110) (P < 0.001). The mean battery life improved in both <3-V cohorts (P < 0.001). Annual reprogramming sessions were reduced in Group A and Group C (P < 0.001). Subset analysis of variance showed no statistical improvement in most patient outcomes when 1-V subjects were compared to 2- and 3-V cohorts. However, 32% of 1-V patients (P < 0.001) noted the onset of severe pelvic/perirectal pain and big toe plantar flexion movement with small increments in voltage (0.1-0.2 V) during reprogramming. Only 7% of 2-V and 1% of 3-V patients experienced this complication. CONCLUSIONS: Significant improvement was noted (up to 40%) in most clinical voiding parameters in the <3-V patients for both OAB and urinary retention. While <3 V will still statistically improve patient outcomes, a voltage <2 V may elicit self-reprogramming pain with severe bellows and plantar flexion movement, which may discourage patients from therapy adjustments. We recommend randomised, controlled trials to confirm these results.

Image restoration in fiber-coupled imagers using space-variant impulse response characterization.

Fiber-coupled image sensors have attracted interest in recent years for high-resolution conformal image transfer, including mapping of the spherical image surface of a monocentric wide-angle lens to one or more flat focal plane sensors. However, image resolution is lost due to fiber bundle defects, moiré from lateral fiber-sensor misalignment, and blur due to the nonzero gap between fiber bundle and the image sensor. Here we investigate whether subpixel impulse response characterization of the strongly shift-variant impulse response can be used with existing image-processing techniques to recover the resolution otherwise lost in image transfer. We show that the submicrometer impulse response is experimentally repeatable, and can be used to recover image data and reveal fine features of the input surface structure of a 2.5 µm pitch fiber bundle.

Folded monocentric imager with deformable mirror focus.

We describe a catadioptric monocentric imager using an elastic central element focused by deformation of a fold mirror. We show the design of 6 mm and 12 mm focal length F/2.8 achromats and compare design performance when focusing by translating the sensor, translating the fold mirror, and by spherically deforming the fold mirror. We tested the 12 mm focal length design using a diamond turned polystyrene element as the outer meniscus lens (and mechanical mount), filled with an optical gel in contact with the central aperture and fold mirror, and demonstrate focusing by mechanical deformation of the fold mirror. The resolution at the spherical image surface was inspected by optical relay imaging, yielding a best focus MTF50 of 52.6 lp/mm.

Angle-invariant imaging using a total internal reflection virtual aperture.

Conventional lens stops, implemented with an absorptive physical aperture, have an angle-dependent projection that introduces field dependent loss and reduces diffraction-limited resolution. Retro-telephoto lenses obtain uniform response using aberration vignetting, but this results in low wide-angle resolution and significant lens volume. However, an angle-independent "virtual" aperture can be created by total internal reflection (TIR) from a thin low index layer inside the lens. We apply this to monocentric wide-angle imaging and find a simple relationship between the filtering layer index and radius and the resulting lens F/#. We provide two detailed designs of lenses with 12 mm focal length and a F/2.5 TIR stop, one using a low index adhesive within a solid fixed-focus lens, the other using an air cavity within an adjustable focus lens. We show the designs provide absolutely uniform resolution and light collection over an angle range of 84° and 106°, respectively, resulting in a dramatic improvement of both light collection and angular resolution per unit volume over conventional wide-angle lenses.

Efficient analysis of deep high-index-contrast gratings under arbitrary illumination.

An efficient method for computing the problem of an electromagnetic beam transmission through deep periodic dielectric gratings is presented. In this method the beam is decomposed into a spectrum of plane waves, transmission coefficients corresponding to each such plane wave are found via Rigorous Coupled Wave Analysis, and the transmitted beam is calculated via inverse Fourier integral. To make the approach efficient for deep gratings the fast variations of the transmission coefficients versus spatial frequency are accounted for analytically by casting the summations and integrals in a form that has explicit rapidly varying exponential terms. The resulting formulation allows computing the transmitted beam with a small number of samples independent of the grating depth.

Enhanced signal coupling in wide-field fiber-coupled imagers.

Some high-performance imaging systems, including wide angle "monocentric" lenses made of concentric spherical shells, form a deeply curved image surface coupled to focal plane sensors by optical fiber bundles with a curved input and flat output face. However, refraction at the angled input facet limits the range of input angles, even for fiber bundles with numerical aperture 1. Here we investigate using a curved beam deflector near the focal surface to increase the field of view and improve spatial resolution at the edges of the field of view. We show the field of view of such an imager can be increased from approximately 60° (full width at half maximum intensity) to over 90° using an embossed refractive microprism array, where the prism angle varies across the aperture to maintain coupling. We describe a proof-of-principle experiment using a f = 17.8mm fiber-coupled monocentric singlet lens, and show that a local region of microprisms embossed into a thin layer of SU-8 photopolymer can increase the field of view by 50%.

Analysis and characterization of high-resolution and high-aspect-ratio imaging fiber bundles.

High-contrast imaging fiber bundles (FBs) are characterized and modeled for wide-angle and high-resolution imaging applications. Scanning electron microscope images of FB cross sections are taken to measure physical parameters and verify the variations of irregular fibers due to the fabrication process. Modal analysis tools are developed that include irregularities in the fiber core shapes and provide results in agreement with experimental measurements. The modeling demonstrates that the irregular fibers significantly outperform a perfectly regular "ideal" array. Using this method, FBs are designed that can provide high contrast with core pitches of only a few wavelengths of the guided light. Structural modifications of the commercially available FB can reduce the core pitch by 60% for higher resolution image relay.

Quantitative analysis and temperature-induced variations of moiré pattern in fiber-coupled imaging sensors.

Imaging fiber bundles can map the curved image surface formed by some high-performance lenses onto flat focal plane detectors. The relative alignment between the focal plane array pixels and the quasi-periodic fiber-bundle cores can impose an undesirable space variant moiré pattern, but this effect may be greatly reduced by flat-field calibration, provided that the local responsivity is known. Here we demonstrate a stable metric for spatial analysis of the moiré pattern strength, and use it to quantify the effect of relative sensor and fiber-bundle pitch, and that of the Bayer color filter. We measure the thermal dependence of the moiré pattern, and the achievable improvement by flat-field calibration at different operating temperatures. We show that a flat-field calibration image at a desired operating temperature can be generated using linear interpolation between white images at several fixed temperatures, comparing the final image quality with an experimentally acquired image at the same temperature.

Wink-controlled polarization-switched telescopic contact lenses.

We describe a wink-controlled hands-free switching system for eye-borne telescopic vision, based on a previously tested fixed-magnification telescope embedded within scleral contact lenses. Here we integrate orthogonal polarizers into the contact lens covering the F/9.1 refractive 1× and F/9.6 catadioptric 2.8× vision paths, to allow switching via external liquid crystal shutters. We provide hands-free control by an infrared wink/blink monitor, using passive retroreflectors embedded within the contact lenses. We demonstrate system operation of the self-contained switching eyewear and the modified contact lenses with a life-size human eye model with mechanical "eyelids."

Wearable telescopic contact lens.

We describe the design, fabrication, and testing of a 1.6 mm thick scleral contact lens providing both 1× and 2.8× magnified vision paths, intended for use as a switchable eye-borne telescopic low-vision aid. The F/9.7 telescopic vision path uses an 8.2 mm diameter annular entrance pupil and 4 internal reflections in a polymethyl methacrylate precision optic. This gas-impermeable insert is contained inside a smooth outer casing of rigid gas-permeable polymer, which also provides achromatic correction for refraction at the curved lens face. The unmagnified F/4.1 vision path is through the central aperture of the lens, with additional transmission between the annular telescope rings to enable peripheral vision. We discuss potential solutions for providing oxygenation for an extended wear version of the lens. The prototype lenses were characterized using a scale-model human eye, and telescope functionality was confirmed in a small-scale clinical (nondispensed) demonstration.

Image processing for cameras with fiber bundle image relay.

Some high-performance imaging systems generate a curved focal surface and so are incompatible with focal plane arrays fabricated by conventional silicon processing. One example is a monocentric lens, which forms a wide field-of-view high-resolution spherical image with a radius equal to the focal length. Optical fiber bundles have been used to couple between this focal surface and planar image sensors. However, such fiber-coupled imaging systems suffer from artifacts due to image sampling and incoherent light transfer by the fiber bundle as well as resampling by the focal plane, resulting in a fixed obscuration pattern. Here, we describe digital image processing techniques to improve image quality in a compact 126° field-of-view, 30 megapixel panoramic imager, where a 12 mm focal length F/1.35 lens made of concentric glass surfaces forms a spherical image surface, which is fiber-coupled to six discrete CMOS focal planes. We characterize the locally space-variant system impulse response at various stages: monocentric lens image formation onto the 2.5 µm pitch fiber bundle, image transfer by the fiber bundle, and sensing by a 1.75 µm pitch backside illuminated color focal plane. We demonstrate methods to mitigate moiré artifacts and local obscuration, correct for sphere to plane mapping distortion and vignetting, and stitch together the image data from discrete sensors into a single panorama. We compare processed images from the prototype to those taken with a 10× larger commercial camera with comparable field-of-view and light collection.