The origin of betaine in mouse oocytes and preimplantation embryos†.

Betaine has important roles in preimplantation mouse embryos, including as an organic osmolyte that functions in cell volume regulation in the early preimplantation stages and as a donor to the methyl pool in blastocysts. The origin of betaine in oocytes and embryos was largely unknown. Here, we found that betaine was present from the earliest stage of growing oocytes. Neither growing oocytes nor early preantral follicles could take up betaine, but antral follicles were able to transport betaine and supply the enclosed oocyte. Betaine is synthesized by choline dehydrogenase, and female mice lacking Chdh did not have detectable betaine in their oocytes or early embryos. Supplementing betaine in their drinking water restored betaine in the oocyte only when supplied during the final stages of antral follicle development but not earlier in folliculogenesis. Together with the transport results, this implies that betaine can only be exogenously supplied during the final stages of oocyte growth. Previous work showed that the amount of betaine in the oocyte increases sharply during meiotic maturation due to upregulated activity of choline dehydrogenase within the oocyte. This betaine present in mature eggs was retained after fertilization until the morula stage. There was no apparent role for betaine uptake via the SIT1 (SLC6A20) betaine transporter that is active at the 1- and 2-cell stages. Instead, betaine was apparently retained because its major route of efflux, the volume-sensitive organic osmolyte - anion channel, remained inactive, even though it is expressed and capable of being activated by a cell volume increase.

Thermo-Magnetostrictive Effect for Driving Antiferromagnetic Two-Dimensional Material Resonators.

Magnetostrictive coupling has recently attracted interest as a sensitive method for studying magnetism in two-dimensional (2D) materials by mechanical means. However, its application in high-frequency magnetic actuators and transducers requires rapid modulation of the magnetic order, which is difficult to achieve with external magnets, especially when dealing with antiferromagnets. Here, we optothermally modulate the magnetization in antiferromagnetic 2D material membranes of metal phosphor trisulfides (MPS3), to induce a large high-frequency magnetostrictive driving force. From the analysis of the temperature-dependent resonance amplitude, we provide evidence that the force is due to a thermo-magnetostrictive effect, which significantly increases near the Neél temperature, due to the strong temperature dependence of the magnetization. By studying its angle dependence, we find the effect is observed to follow anisotropic magnetostriction of the crystal lattice. The results show that the thermo-magnetostrictive effect results in a strongly enhanced thermal expansion force near the critical temperature of magnetostrictive 2D materials, which can enable more efficient actuation of nano-magnetomechanical devices and can also provide a route for studying the high-frequency coupling among magnetic, mechanical, and thermodynamic degrees of freedom down to the 2D limit.

The Telemedicine Demand Index and its Utility in Managing COVID-19 Case Surges.

Introduction: Telemedicine was an integral component in Singapore's COVID-19 management strategy, having been deployed at a national level in a centrally-administered program whereby patients at higher risk of developing severe COVID-19 disease were proactively assigned tele-consultations, whereas those at lower risk and seen by primary care physicians could request ad hoc tele-consultations. To better plan for fluctuations in telemedicine demand during the pandemic, the Telemedicine Demand Index (TDI) was developed. Methods: Three main factors influencing telemedicine demand were considered-characteristics of the Variant of Concern, prevailing health care policies, and the population's healthcare-seeking behaviour-from which 11 coefficients were derived for the TDI formula. The number of tele-consultations demanded is the product of the TDI and the total number of new COVID-19 cases for a given period. Results: Real-world data from January 31 to March 27, 2022 were compared with TDI estimates. A total of 148,485 tele-consultations were conducted against a backdrop of 723,675 new COVID-19 cases for the period. The TDI overestimated demand by an average 11.4%. Data from March 28 to May 1, 2022 were then used to derive new TDI values and applied to a 3-week period starting May 9, 2022, following a policy change. A total of 5,560 tele-consultations were conducted against a backdrop of 77,998 new COVID-19 cases. The TDI underestimated demand by an average of 7.2%. Conclusion: The TDI shows initial promise for quickly estimating telemedicine demand at a population level. By leveraging historical data and applying some informed assumptions, it allows for the estimation of current capabilities and future requirements. There remains scope for more research to refine the TDI's constituent components, as well as its applicability in different population contexts.

Interlaboratory comparison of Pseudomonas aeruginosa phage susceptibility testing.

Standardized approaches to phage susceptibility testing (PST) are essential to inform selection of phages for study in patients with bacterial infections. There is no reference standard for assessing bacterial susceptibility to phage. We compared agreement between PST performed at three centers: two centers using a liquid assay standardized between the sites with the third, a plaque assay. Four Pseudomonas aeruginosa phages: PaWRA01ø11 (EPa11), PaWRA01ø39 (EPa39), PaWRA02ø83 (EPa83), PaWRA02ø87 (EPa87), and a cocktail of all four phages were tested against 145 P. aeruginosa isolates. Comparisons were made within measurements at the two sites performing the liquid assay and between these two sites. Agreement was assessed based on coverage probability (CP8), total deviation index, concordance correlation coefficient (CCC), measurement accuracy, and precision. For the liquid assay, there was satisfactory agreement among triplicate measurements made on different days at site 1, and high agreement based on accuracy and precision between duplicate measurements made on the same run at site 2. There was fair accuracy between measurements of the two sites performing the liquid assay, with CCCs below 0.6 for all phages tested. When compared to the plaque assay (performed once at site 3), there was less agreement between results of the liquid and plaque assays than between the two sites performing the liquid assay. Similar findings to the larger group were noted in the subset of 46 P. aeruginosa isolates from cystic fibrosis. Results of this study suggest that reproducibility of PST methods needs further development.

Low phase noise operation of a cavity-stabilized 698†nm AlGaInP-based VECSEL.

We report for the first time a high performance, single frequency AlGaInP-based VECSEL (vertical-external-cavity surface-emitting-laser) with emission at 698 nm, targeting the clock transition of neutral strontium atoms. Furthermore, we present comprehensive noise characterization of this class-A semiconductor laser, including the residual fast phase noise in addition to the frequency and relative intensity noise. The low noise VECSEL has output power at around 135 mW with an estimated linewidth of 115 Hz when frequency stabilized via the Pound-Drever-Hall (PDH) technique to a high finesse reference cavity, without intermediate stabilization. The phase noise is measured to be below -126 dBc/Hz for frequencies between 10 kHz and 15 MHz with a total integrated phase noise of 3.2 mrad, suitable not only for ultra-cold neutral strontium-based quantum technologies, such as optical clocks, but also with potential for atom-interferometry applications.

Monolithic VECSEL for stable kHz linewidth.

Vertical-external-cavity surface-emitting semiconductor lasers (VECSELs) are of increasing interest for applications requiring ultra-coherence and/or low noise at novel wavelengths; performance that is currently achieved via high-Q, air-spaced resonators to achieve long intra-cavity photon lifetimes (for the so-called class-A low noise regime), power scaling and high beam quality. Here, we report on the development of a compact, electronically tunable, monolithic-cavity, class-A VECSEL (monolithic VECSEL) for ultra-narrow free-running linewidths. A multi-quantum-well, resonant periodic gain structure with integrated distributed Bragg reflector (DBR) was optically-bonded to an air-gap-free laser resonator created inside a right-angle fused-silica prism to suppress the influence of environmental noise on the external laser oscillation, thus achieving high stability. Mode-hop-free wavelength tuning is performed via the stabilized temperature; or electronically, and with low latency, via a shear piezo-electric transducer mounted on the top of the prism. The free-running linewidth, estimated via the frequency power spectral density (PSD), is sub-kHz over ms timescales and <1.9 kHz for time sampling as long as 1s, demonstrating at least two orders-of-magnitude improvement in noise performance compared to previously reported single frequency VECSELs. The stable, total internal reflection resonator concept is akin to the prevalent monolithic non-planar ring oscillator (NPRO), however the monolithic VECSEL has several important advantages: tailored emission wavelength (via semiconductor bandgap engineering), no relaxation oscillations, no applied magnetic field, and low requirements on the pump beam quality. This approach is power-scalable in principle and could be applied to VECSELs at any of the wavelengths from the visible to the mid-infrared at which they are already available, to create a range of robust, ultra-coherent laser systems with reduced bulkiness and complexity. This is of particular interest for remote metrology and the translation of quantum technologies, such as optical clocks, from research laboratories into real world applications.

Stretching the Bisalkyne Raman Spectral Palette Reveals a New Electrophilic Covalent Motif.

Small heteroaryl-diyne (Het-DY) tags with distinct vibrational frequencies, and physiologically relevant cLog P were designed for multiplexed bioorthogonal Raman imaging. Pd-Cu catalyzed coupling, combined with the use of Lei ligand, was shown to improve overall yields of the desired heterocoupled Het-DY tags, minimizing the production of homocoupled side-products. Spectral data were in agreement with the trends predicted by DFT calculations and systematic introduction of electron- rich/poor rings stretched the frequency limit of aryl-capped diynes (2209-2243 cm-1 ). The improved Log P of these Het-DY tags was evident from their diffuse distribution in cellular uptake studies and functionalizing tags with organelle markers allowed the acquisition of location-specific biological images. LC-MS- and NMR-based assays showed that some heteroaryl-capped internal alkynes are potential nucleophile traps with structure-dependent reactivity. These biocompatible Het-DY tags, equipped with covalent reactivity, open up new avenues for Raman bioorthogonal imaging.

Ask and Ask Again: Repeated Screening for Smoking Increases Likelihood of Prescription for Cessation Treatment Among Women Veterans.

BACKGROUND: Preventive screening at the point of care can increase desired clinical outcomes. However, the impact of repeated screening for tobacco use on receiving smoking cessation treatment among women Veteran population has not been documented. OBJECTIVE: To examine screening for tobacco use using clinical reminders and the association between the number of screenings and prescription for cessation treatment. DESIGN: A retrospective analysis using data from a 5-year implementation trial for cardiovascular risk identification conducted between December 2016 and March 2020. SUBJECTS: Women patients who had at least one primary care visit with a women's health provider during the study period at five primary care clinics in the Veterans Affairs (VA) Healthcare System. MEASURES: The outcome is prescription of pharmacotherapy or referral to behavioral counseling for smoking cessation on or after the screening date. The exposure is the number of screenings for tobacco use from the trial and the annual VA national clinical reminders during the study period. RESULTS: Of 6009 eligible patients, 5788 (96.3%) were screened at least once for tobacco use over five calendar years, and 2784 of those screened (48.1%) were reported as current and former smokers. Among current and former smokers, 709 (25.5%) received a prescription and/or referral for smoking cessation. In the adjusted model, the average predicted probability of prescription and/or referral for smoking cessation was 13.7% among current and former smokers screened once over 5 years, 18.6% among screened twice, 26.5% among screened thrice, 32.9% among screened four times, and 41.7% among screened five or six times. CONCLUSIONS: Repeated screening was associated with higher predicted probabilities of being prescribed smoking cessation treatment.

A microbiome-targeting fibre-enriched nutritional formula is well tolerated and improves quality of life and haemoglobin A1c in type 2 diabetes: A double-blind, randomized, placebo-controlled trial.

AIMS: To investigate a prebiotic fibre-enriched nutritional formula on health-related quality of life and metabolic control in type 2 diabetes. MATERIALS AND METHODS: This was a 12-week, double-blind, placebo-controlled study with an unblinded dietary advice only comparator arm. Participants were randomized 2:1:1 to a prebiotic fibre-enriched nutritional formula (Active), a placebo fibre-absent nutritional formula (Placebo), or non-blinded dietary advice alone (Diet). Primary endpoint was change in core Type 2 Diabetes Distress Assessment System (cT2-DDAS) at week 12. Glycated haemoglobin (HbA1c) change was a key secondary endpoint. RESULTS: In total, 192 participants were randomized. Mean age was 54.3 years, HbA1c 7.8%, and body mass index 35.9 kg/m2 . At week 12, cT2-DDAS reduced significantly in Active versus Placebo (-0.4, p = .03), and HbA1c was reduced significantly in Active vs Placebo (-0.64%, p = .01). Gut microbiome sequencing revealed that the relative abundance of two species of butyrate-producing bacteria (Roseburia faecis and Anaerostipes hadrus) increased significantly in Active vs. Placebo. CONCLUSIONS: A microbiome-targeting nutritional formula significantly improved cT2-DDAS and HbA1c, suggesting the potential for prebiotic fibre as a complement to lifestyle and/or pharmaceutical interventions for managing type 2 diabetes.

A Compact Ultra-Wideband Monocone Antenna with Folded Shorting Wires for Vehicle-to-Everything (V2X) Applications.

In this paper, a capacitively-fed, ultra-wideband (UWB), and low-profile monocone antenna is proposed for vehicle-to-everything (V2X) applications. The proposed antenna consists of a monocone design with an inner set of vias. Additionally, an outer ring is added with a small gap from the monocone and shorted with six folded wires of different lengths to extend the operating band. The proposed antenna covers the frequency range from 0.75 GHz to 7.6 GHz and has a 164% fractional bandwidth, with a gain value varying between 2 and 10 dBi. The dimensions of the antenna are 0.37λL × 0.37λL × 0.067λL. The antenna was fabricated using a 3D printer with low-cost polylactic acid plastic (PLA) material and then sprayed with aerosol copper nanoparticles. The efficiency was approximately 90% throughout the frequency bands of interest. Finally, the proposed antenna was installed on a vehicle and tested with an OBU (onboard unit) and a RSU (roadside unit) in the field. The results show a longer wireless communication range for V2X applications.

Tunable Strong Coupling of Mechanical Resonance between Spatially Separated FePS3 Nanodrums.

Coupled nanomechanical resonators made of two-dimensional materials are promising for processing information with mechanical modes. However, the challenge for these systems is to control the coupling. Here, we demonstrate strong coupling of motion between two suspended membranes of the magnetic 2D material FePS3. We describe a tunable electromechanical mechanism for control over both the resonance frequency and the coupling strength using a gate voltage electrode under each membrane. We show that the coupling can be utilized for transferring data between drums by amplitude modulation. Finally, we also study the temperature dependence of the coupling and how it is affected by the antiferromagnetic phase transition characteristic of this material. The presented electrical coupling of resonant magnetic 2D membranes holds the promise of transferring mechanical energy over a distance at low electrical power, thus enabling novel data readout and information processing technologies.

Self-Sealing Complex Oxide Resonators.

Although 2D materials hold great potential for next-generation pressure sensors, recent studies revealed that gases permeate along the membrane-surface interface, necessitating additional sealing procedures. In this work, we demonstrate the use of free-standing complex oxides as self-sealing membranes that allow the reference cavity beneath to be sealed by a simple anneal. To test the hermeticity, we study the gas permeation time constants in nanomechanical resonators made from SrRuO3 and SrTiO3 membranes suspended over SiO2/Si cavities which show an improvement up to 4 orders of magnitude in the permeation time constant after annealing the devices. Similar devices fabricated on Si3N4/Si do not show such improvements, suggesting that the adhesion increase over SiO2 is mediated by oxygen bonds that are formed at the SiO2/complex oxide interface during the self-sealing anneal. Picosecond ultrasonics measurements confirm the improvement in the adhesion by 70% after annealing.

Enhanced Monitoring System to Better Monitor High-Risk COVID-19 Patients.

Telemedicine (TM) is a useful tool to extend medical care during a pandemic. TM was extensively utilized in Singapore during the COVID-19 pandemic as part of the Nation's COVID-19 healthcare strategy. Patients were risk stratified to prioritize limited healthcare resources and the Telemedicine Allocation Reconciliation System (TMARS) was adapted to monitor and manage limited TM resources. High-Risk patients (Protocol 1) had an escalation rate of 4.87%, compared to the non-High-Risk patients' 0.002% and TM doctors spent an average of six hours to complete one tele-consultation. In order to optimize the efficiency of the TM system, an enhanced monitoring system was implemented in March 2022. The intent was to focus monitoring efforts on the High-Risk patients. High-Risk patients reporting sick for the first time were prioritized to receive tele-consultations through this system. With the aid of a data-driven dashboard, the Operations Control and Monitoring team (OCM) was able to closely monitor the performance of the various TM providers (TMPs), sent them timely reminders and re-assigned patients to other TMPs when the requisite turnaround time was not met. Implementing the enhanced monitoring system resulted in a significant reduction in the average time taken to provide tele-consultations. After 3 months of implementation, the percentages of consultations completed within two hours were raised from 75.7% (February 2022) to 96.8% (May 2022), greatly increasing productivity and efficiency.

The Coordination Toolkit and Coaching Project: Cluster-Randomized Quality Improvement Initiative to Improve Patient Experience of Care Coordination.

BACKGROUND: Given persistent gaps in coordination of care for medically complex primary care patients, efficient strategies are needed to promote better care coordination. OBJECTIVE: The Coordination Toolkit and Coaching project compared two toolkit-based strategies of differing intensity to improve care coordination at VA primary care clinics. DESIGN: Multi-site, cluster-randomized QI initiative. PARTICIPANTS: Twelve VA primary care clinics matched in 6 pairs. INTERVENTIONS: We used a computer-generated allocation sequence to randomize clinics within each pair to two implementation strategies. Active control clinics received an online toolkit with evidence-based tools and QI coaching manual. Intervention clinics received the online toolkit plus weekly assistance from a distance coach for 12 months. MAIN MEASURES: We quantified patient experience of general care coordination using the Health Care System Hassles Scale (primary outcome) mailed at baseline and 12-month follow-up to serial cross-sectional patient samples. We measured the difference-in-difference (DiD) in clinic-level-predicted mean counts of hassles between coached and non-coached clinics, adjusting for clustering and patient characteristics using zero-inflated negative binomial regression and bootstrapping to obtain 95% confidence intervals. Other measures included care coordination QI projects attempted, tools adopted, and patient-reported exposure to projects. KEY RESULTS: N = 2,484 (49%) patients completed baseline surveys and 2,481 (48%) completed follow-ups. Six coached clinics versus five non-coached clinics attempted QI projects. All coached clinics versus two non-coached clinics attempted more than one project or projects that were multifaceted (i.e., involving multiple components addressing a common goal). Five coached versus three non-coached clinics used 1-2 toolkit tools. Both the coached and non-coached clinics experienced pre-post reductions in hassle counts over the study period (- 0.42 (- 0.76, - 0.08) non-coached; - 0.40 (- 0.75, - 0.06) coached). However, the DiD (0.02 (- 0.47, 0.50)) was not statistically significant; coaching did not improve patient experience of care coordination relative to the toolkit alone. CONCLUSION: Although coached clinics attempted more or more complex QI projects and used more tools than non-coached clinics, coaching provided no additional benefit versus the online toolkit alone in patient-reported outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03063294.

Measuring Gender Role Conflict, Internalized Stigma, and Racial and Sexual Identity in Behaviorally Bisexual Black Men.

Black men who have sex with men and women (BMSMW) experience pressure to fill hypermasculine ideals and may not identify with "gay" cultural norms. Existing measures of gender role expectations and internalized homophobia are not culturally appropriate for BMSMW. Researchers generally measure categorical identification with race, gender, and sexual orientation groups separately, whereas BMSMW may identify with multiple categories. We modified the Gender Role Conflict Scale to create the M-GRCS and the Internalized Homophobia Scale to include biphobia (Internalized Bi/Homophobia Scale, IBHS). To examine identification at the intersection of race, gender, and sexual orientation, we created 11 Integrated Race and Sexuality Scale (IRSS) items. With data from 429 BMSMW, we conducted exploratory factor analysis of the 59 items using categorical principal axis factoring with unweighted least squares extraction and Promax factor rotation. We created simple-summated multi-item scales and evaluated their construct validity. The rotated solution yielded four factors with 47 items and a simple factor structure: M-GRCS defined two factors (α = .93 for restricted emotionality/affection; .87 for success/power/competition); the IBHS (α = .89) and IRSS (α = .74) each defined a single factor. The IRSS factor was positively correlated with the Lukwago Racial Pride Scale, r(417) = .40. The IBHS factor was negatively correlated with the IRSS factor, r(414) = - .22. The two M-GRCS factors suggest that the construct of hypermasculinity impacts BMSMW. The high IBHS reliability indicates that homophobia and biphobia were positively correlated in this sample. These three scales have potential for future studies with BMSMW.

Chemical Design and Magnetic Ordering in Thin Layers of 2D Metal-Organic Frameworks (MOFs).

Through rational chemical design, and thanks to the hybrid nature of metal-organic frameworks (MOFs), it is possible to prepare molecule-based 2D magnetic materials stable at ambient conditions. Here, we illustrate the versatility of this approach by changing both the metallic nodes and the ligands in a family of layered MOFs that allows the tuning of their magnetic properties. Specifically, the reaction of benzimidazole-type ligands with different metal centers (MII = Fe, Co, Mn, Zn) in a solvent-free synthesis produces a family of crystalline materials, denoted as MUV-1(M), which order antiferromagnetically with critical temperatures that depend on M. Furthermore, the incorporation of additional substituents in the ligand results in a novel system, denoted as MUV-8, formed by covalently bound magnetic double layers interconnected by van der Waals interactions, a topology that is very rare in the field of 2D materials and unprecedented for 2D magnets. These layered materials are robust enough to be mechanically exfoliated down to a few layers with large lateral dimensions. Finally, the robustness and crystallinity of these layered MOFs allow the fabrication of nanomechanical resonators that can be used to detect─through laser interferometry─the magnetic order in thin layers of these 2D molecule-based antiferromagnets.

Repair of an Attenuated Low-Passage Murine Cytomegalovirus Bacterial Artificial Chromosome Identifies a Novel Spliced Gene Essential for Salivary Gland Tropism.

The cloning of herpesviruses as bacterial artificial chromosomes (BACs) has revolutionized the study of herpesvirus biology, allowing rapid and precise manipulation of viral genomes. Several clinical strains of human cytomegalovirus (HCMV) have been cloned as BACs; however, no low-passage strains of murine CMV (MCMV), which provide a model mimicking these isolates, have been cloned. Here, the low-passage G4 strain of was BAC cloned. G4 carries an m157 gene that does not ligate the natural killer (NK) cell-activating receptor, Ly49H, meaning that unlike laboratory strains of MCMV, this virus replicates well in C57BL/6 mice. This BAC clone exhibited normal replication during acute infection in the spleen and liver but was attenuated for salivary gland tropism. Next-generation sequencing revealed a C-to-A mutation at nucleotide position 188422, located in the 3' untranslated region of sgg1, a spliced gene critical for salivary gland tropism. Repair of this mutation restored tropism for the salivary glands. Transcriptional analysis revealed a novel spliced gene within the sgg1 locus. This small open reading frame (ORF), sgg1.1, starts at the 3' end of the first exon of sgg1 and extends exon 2 of sgg1. This shorter spliced gene is prematurely terminated by the nonsense mutation at nt 188422. Sequence analysis of tissue culture-passaged virus demonstrated that sgg1.1 was stable, although other mutational hot spots were identified. The G4 BAC will allow in vivo studies in a broader range of mice, avoiding the strong NK cell responses seen in B6 mice with other MCMV BAC-derived MCMVs.IMPORTANCE Murine cytomegalovirus (MCMV) is widely used as a model of human CMV (HCMV) infection. However, this model relies on strains of MCMV that have been serially passaged in the laboratory for over four decades. These laboratory strains have been cloned as bacterial artificial chromosomes (BACs), which permits rapid and precise manipulation. Low-passage strains of MCMV add to the utility of the mouse model of HCMV infection but do not exist as cloned BACs. This study describes the first such low-passage MCMV BAC. This BAC-derived G4 was initially attenuated in vivo, with subsequent full genomic sequencing revealing a novel spliced transcript required for salivary gland tropism. These data suggest that MCMV, like HCMV, undergoes tissue culture adaptation that can limit in vivo growth and supports the use of BAC clones as a way of standardizing viral strains and minimizing interlaboratory strain variation.

Efficacy and safety of subcutaneous prophylaxis with dalcinonacog alfa in adults with haemophilia B.

AIM: Phase 2b study to assess efficacy, safety, thrombogenicity, immunogenicity and tolerability with 28 days of daily dosing of subcutaneous (SQ) dalcinonacog alfa as prophylaxis for haemophilia B (HB). METHODS: Adult males with a confirmed diagnosis of congenital HB (factor IX [FIX] activity <2%) received daily dalcinonacog alfa 100 IU/kg SQ until day 28. The primary efficacy endpoint was the number of participants who achieved a steady-state FIX activity level ≥12%. Tolerability, thrombogenicity and immunogenicity were study safety endpoints. RESULTS: Of 6 participants who received study drug, one discontinued the study on day 7 due to injection-site reactions (ISR). Of the 5 participants completing the study, FIX activity level exceeded 12% in 3 participants at day 7, increasing to 4 participants on days 14, 21 and 28 and all 5 at day 29. Pharmacokinetic findings (including mean alpha and beta half-life of 5.3 days and 3.9 days, respectively, and mean residence time of 6.2 days) supported prolonged effects. Thrombogenicity markers remained normal throughout prophylactic injections or showed some initial increases followed by decreases with continued dosing. Two participants had anti-drug antibodies to dalcinonacog alfa at study end, none had neutralizing antibody. Two participants had ISR, both resolved. Reports of redness, swelling, tenderness or pain among the first 3 participants prompted dose-splitting for the last 3 participants, leading to fewer ISR. CONCLUSION: Subcutaneous dalcinonacog alfa is effective in raising FIX levels into the mild haemophilia range, comparable to intravenous extended half-life FIX clotting factors.

Recent advances in the use of stimulated Raman scattering in histopathology.

Stimulated Raman histopathology (SRH) utilises the intrinsic vibrational properties of lipids, proteins and nucleic acids to generate contrast providing rapid image acquisition that allows visualisation of histopathological features. It is currently being trialled in the intraoperative setting, where the ability to image unprocessed samples rapidly and with high resolution offers several potential advantages over the use of conventional haematoxylin and eosin stained images. Here we review recent advances in the field including new updates in instrumentation and computer aided diagnosis. We also discuss how other non-linear modalities can be used to provide additional diagnostic contrast which together pave the way for enhanced histopathology and open up possibilities for in vivo pathology.

A Mechanically Tunable Quantum Dot in a Graphene Break Junction.

Graphene quantum dots (QDs) are intensively studied as platforms for the next generation of quantum electronic devices. Fine tuning of the transport properties in monolayer graphene QDs, in particular with respect to the independent modulation of the tunnel barrier transparencies, remains challenging and is typically addressed using electrostatic gating. We investigate charge transport in back-gated graphene mechanical break junctions and reveal Coulomb blockade physics characteristic of a single, high-quality QD when a nanogap is opened in a graphene constriction. By mechanically controlling the distance across the newly formed graphene nanogap, we achieve reversible tunability of the tunnel coupling to the drain electrode by 5 orders of magnitude, while keeping the source-QD tunnel coupling constant. The break junction device can therefore become a powerful platform to study the physical parameters that are crucial to the development of future graphene-based devices, including energy converters and quantum calorimeters.