Optical penetration models for practical prediction of femtosecond laser ablation of dental hard tissue.

OBJECTIVES: To develop and practically test high-precision femtosecond laser ablation models for dental hard tissue that are useful for detailed planning of automated laser dental restorative treatment. METHODS: Analytical models are proposed, derived, and demonstrated for practical calculation of ablation rates, ablation efficiency and ablated morphology of human dental enamel and dentin using femtosecond lasers. The models assume an effective optical attenuation coefficient for the irradiated material. To achieve ablation, it is necessary for the local energy density of the attenuated pulse in the hard tissue to surpass a predefined threshold that signifies the minimum energy density required for material ionization. A 1029 nm, 40 W carbide 275 fs laser was used to ablate sliced adult human teeth and generate the data necessary for testing the models. The volume of material removed, and the shape of the ablated channel were measured using optical profilometry. RESULTS: The models fit with the measured ablation efficiency curve against laser fluence for both enamel and dentin, correctly capturing the fluence for optimum ablation and the volume of ablated material per pulse. The detailed shapes of a 400-micrometer wide channel and a single-pulse width channel are accurately predicted using the superposition of the analytical result for a single pulse. CONCLUSIONS: The findings have value for planning automated dental restorative treatment using femtosecond lasers. The measurements and analysis give estimates of the optical properties of enamel and dentin irradiated with an infrared femtosecond laser at above-threshold fluence and the proposed models give insight into the physics of femtosecond laser processing of dental hard tissue.

Subfemtowatt Laser Phase Tracking.

Low power optical phase tracking is an enabling capability for intersatellite laser interferometry, as minimum trackable power places significant constraints on mission design. Through the combination of laser stabilization and control-loop parameter optimization, we have demonstrated continuous tracking of a subfemtowatt optical field with a mean time between slips of more than 1000 s. Comparison with analytical models and numerical simulations verified that the observed experimental performance was limited by photon shot noise and unsuppressed laser frequency fluctuations. Furthermore, with two stabilized lasers, we have demonstrated 100 min of continuous phase tracking of Gravity Recovery and Climate Experiment (GRACE)-like signal dynamics with an optical carrier ranging in power between 1-7 fW with zero cycle slips. These results indicate the feasibility of future interspacecraft laser links operating with significantly reduced received optical power.

Absolute frequency readout derived from ULE cavity for next generation geodesy missions: erratum.

We found a calculation error affecting the scaling of results presented in Figure 7 of our article "Absolute frequency readout derived from ULE cavity for next generation geodesy missions" [Opt. Express2926014 (2021)10.1364/OE.434483] . The corrected Figure 7 is published here.

A Multicenter Randomized Controlled Trial Comparing Safety, Efficacy, and Cost-effectiveness of the Surgisis Anal Fistula Plug Versus Surgeon's Preference for Transsphincteric Fistula-in-Ano: The FIAT Trial.

OBJECTIVE: To undertake a randomized comparison of the Biodesign Surgisis anal fistula plug against surgeon's preference in treating cryptoglandular transsphincteric fistula-in-ano. SUMMARY BACKGROUND DATA: The efficacy of the Biodesign Surgisis anal fistula plug in healing anal fistulae is uncertain. METHODS: Participants were randomized to the fistula plug with surgeon's preference (advancement flap, cutting seton, fistulotomy, Ligation of the Intersphincteric Fistula Tract procedure). The primary outcome was faecal incontinence quality of life (FIQoL) at 12-months. Secondary outcomes were fistula healing, incontinence rates, and complication and reintervention rates. RESULTS: Between May 2011 and March 2016, 304 participants were randomized to fistula plug or surgeon's preference. No differences were seen in FIQoL between the 2 groups at 12 months. Clinical fistula healing was reported in 66/122 (54%) of the fistula plug and 66/119 (55%) of the surgeon's preference groups at 12 months. Fecal incontinence rates improved marginally in both the groups. Complications and reinterventions were frequent, with significantly more complications in the fistula plug group at 6-weeks (49/142, 35% vs 25/137, 18%; P=0.002). The mean total costs were £2738 (s.d. £1151) for the fistula plug and £2308 (s.d. £1228) for the surgeon's preference group (mean difference +£430, P=0.0174). The average total quality adjusted life years (QALYs) gained was marginally higher in the fistula plug group. The fistula plug was 35% to 45% likely to be cost-effective across a willingness to pay threshold of £20,000 to £30,000 / QALY. CONCLUSIONS: The Biodesign Surgisis anal fistula plug is associated with similar FIQoL and healing rates to surgeon's preference at 12 months. Higher costs and highly uncertain gains in QALYs mean that the fistula plug may not be considered as a cost-effective treatment in the UK NHS.

Detection statistics for coherent RMCW LiDAR.

This paper presents an analytical model and experimental validation for the detection performance and false-alarm rates for phase-encoded random modulation continuous-wave (RMCW) LiDAR. Derivation of the model focuses on propagating the effects of relevant noise sources through the system to determine an analytical expression for the detection rate, expressed by the probability of detection. The model demonstrates that probability of detection depends only on three factors: i) the mean signal-to-noise ratio (SNR) of the measurement; ii) the measurement integration time; and iii) speckle-induced intensity noise. The predicted analytical relationship between measurement SNR and probability of detection was validated by numerical simulations and experimental demonstrations in both a controlled fiber channel and under fully-developed speckle conditions in an uncontrolled free-space channel.

Absolute frequency readout derived from ULE cavity for next generation geodesy missions.

The next generation of Gravity Recovery and Climate Experiment (GRACE)-like dual-satellite geodesy missions proposals will rely on inter-spacecraft laser interferometry as the primary instrument to recover geodesy signals. Laser frequency stability is one of the main limits of this measurement and is important at two distinct timescales: short timescales over 10-1000 seconds to measure the local gravity below the satellites, and at the month to year timescales, where the subsequent gravity measurements are compared to indicate loss or gain of mass (or water and ice) over that period. This paper demonstrates a simple phase modulation scheme to directly measure laser frequency change over long timescales by comparing an on-board Ultra-Stable Oscillator (USO) clocked frequency reference to the Free Spectral Range (FSR) of the on-board optical cavity. By recording the fractional frequency variations the scale correction factor may be computed for a laser locked to a known longitudinal mode of the optical cavity. The experimental results demonstrate a fractional absolute laser frequency stability at the 10 ppb level (10-8) at time scales greater than 10 000 seconds, likely sufficient for next generation mission requirements.

High stability laser locking to an optical cavity using tilt locking.

This paper describes, to our knowledge, the first demonstration of high performance tilt locking, a method of stabilizing laser frequency to an optical reference cavity using a spatial-mode readout technique. The experiment utilized a traveling wave cavity with a finesse of approximately 10,000, housed in a thermally controlled vacuum chamber. The tilt locking method in a double pass configuration has promising performance in the 100 µHz-1 Hz band, including surpassing the Gravity Recovery and Climate Experiment (GRACE) Follow-On laser ranging interferometer requirement. Tilt locking offers a number of benefits such as high sensitivity, low cost, and simple implementation and therefore should be considered for future applications requiring high performance laser locking, such as future laser-based satellite geodesy missions and the Laser Interferometer Space Antenna.

Biological variation of measured and estimated glomerular filtration rate in patients with chronic kidney disease.

When assessing changes in glomerular filtration rate (GFR) it is important to differentiate pathological change from intrinsic biological and analytical variation. GFR is measured using complex reference methods (e.g., iohexol clearance). In clinical practice measurement of creatinine and cystatin C are used in the Modification of Diet in Renal Disease [MDRD] or Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equations to provide estimated GFR. Here we studied the biological variability of measured and estimated GFR in twenty nephrology outpatients (10 male, 10 female; median age 71, range 50-80 years) with moderate CKD (GFR 30-59 ml/min per 1.73 m2). Patients underwent weekly GFR measurement by iohexol clearance over four consecutive weeks. Simultaneously, GFR was estimated using the MDRD, CKD-EPIcreatinine, CKD-EPIcystatinC and CKD-EPIcreatinine+cystatinC equations. Within-subject biological variation expressed as a percentage [95% confidence interval] for the MDRD (5.0% [4.3-6.1]), CKD-EPIcreatinine (5.3% [4.5-6.4]), CKD-EPIcystatinC (5.3% [4.5-6.5]), and CKD-EPIcreatinine+cystatinC (5.0% [4.3-6.2]) equations were broadly equivalent. The within-subject biological variation for MDRD and CKD- EPIcreatinine+cystatinC estimated GFR were each significantly lower than that of the measured GFR (6.7% [5.6-8.2]). Reference change values, the point at which a true change in a biomarker in an individual can be inferred to have occurred with 95% probability were calculated. By the MDRD equation, positive and negative reference change values were 15.1% and 13.1% respectively. If an individual's baseline MDRD estimated GFR (ml/min per 1.73 m2) was 59, significant increases or decreases would be to values over 68 or under 51 respectively. Within-subject variability of estimated GFR was lower than measured GFR. Reference change values can be used to understand GFR changes in clinical practice. Thus, estimates of GFR are at least as reliable as measured GFR for monitoring patients over time.

High power compatible internally sensed optical phased array.

The technical embodiment of the Huygens-Fresnel principle, an optical phased array (OPA) is an arrangement of optical emitters with relative phases controlled to create a desired beam profile after propagation. One important application of an OPA is coherent beam combining (CBC), which can be used to create beams of higher power than is possible with a single laser source, especially for narrow linewidth sources. Here we present an all-fiber architecture that stabilizes the relative output phase by inferring the relative path length differences between lasers using the small fraction of light that is back-reflected into the fiber at the OPA's glass-air interface, without the need for any external sampling optics. This architecture is compatible with high power continuous wave laser sources (e.g., fiber amplifiers) up to 100 W per channel. The high-power compatible internally sensed OPA was implemented experimentally using commercial 15 W fiber amplifiers, demonstrating an output RMS phase stability of λ/194, and the ability to steer the beam at up to 10 kHz.

Retroreflector for GRACE follow-on: Vertex vs. point of minimal coupling.

The GRACE Follow-On mission will monitor fluctuations in Earth's geoid using, for the first time, a Laser Ranging Interferometer to measure intersatellite distance changes. We have investigated the coupling between spacecraft rotation and the intersatellite range measurement that is incurred due to manufacturing and assembly tolerances of the Triple Mirror Assembly (TMA), a precision retroreflector to ensure alignment between in- and outgoing laser beams. The three TMA mirror planes intersect in a virtual vertex to which satellite displacements are referenced. TMA manufacturing tolerances degrade this ideal vertex, however, a Point of Minimal Coupling (PMC) between spacecraft rotation and displacement exists. This paper presents the experimental location of the PMC under pitch and yaw rotations for a prototype TMA. Rotations are performed using a hexapod, while displacements are monitored with heterodyne laser interferometry to verify the PMC position. Additionally, the vertex of the three TMA mirror planes is measured using a Coordinate Measuring Machine and compared to the PMC position. In the pitch and yaw axes, the biggest deviation between TMA vertex and PMC was 50 ± 64 µm. Thus, within the measurement uncertainties, no difference between TMA vertex and PMC could be observed. This is a key piece of information for integration of the TMA into the spacecraft: It is sufficient to use the readily-available TMA vertex location to ensure minimal rotation-to-displacement coupling during the mission.

Weak-light phase tracking with a low cycle slip rate.

The Gravity Recovery and Climate Experiment Follow-On mission will use a phase-locked loop to track changes in the phase of an optical signal that has been transmitted hundreds of kilometers between two spacecraft. Beam diffraction significantly reduces the received signal power, making it difficult to track, as the phase-locked loop is more susceptible to cycle slips. The lowest reported weak-light phase locking is at 40 fW with a cycle slip rate of 1 cycle per second. By selecting a phase-locked loop bandwidth that minimized the signal variance due to shot noise and laser phase fluctuations, a 30 fW signal has been tracked with a cycle slip rate less than 0.01 cycles per second. This is tracking at a power 25% lower with a 100-fold improvement in the cycle slip rate. This capability will enable a new class of missions, opening up new opportunities for space-based interferometry.

Coherent beam combining using a 2D internally sensed optical phased array.

Coherent combination of multiple lasers using an optical phased array (OPA) is an effective way to scale optical intensity in the far field beyond the capabilities of single fiber lasers. Using an actively phase locked, internally sensed, 2D OPA we demonstrate over 95% fringe visibility of the interfered beam, λ/120 RMS output phase stability over a 5 Hz bandwidth, and quadratic scaling of intensity in the far field using three emitters. This paper presents a new internally sensed OPA architecture that employs a modified version of digitally enhanced heterodyne interferometry (DEHI) based on code division multiplexing to measure and control the phase of each emitter. This internally sensed architecture can be implemented with no freespace components, offering improved robustness to shock and vibration exhibited by all-fiber devices. To demonstrate the concept, a single laser is split into three channels/emitters, each independently controlled using separate electro-optic modulators. The output phase of each channel is measured using DEHI to sense the small fraction of light that is reflected back into the fiber at the OPA's glass-air interface. The relative phase between emitters is used to derive the control signals needed to stabilize their relative path lengths and maintain coherent combination in the far field.

The eGFR-C study: accuracy of glomerular filtration rate (GFR) estimation using creatinine and cystatin C and albuminuria for monitoring disease progression in patients with stage 3 chronic kidney disease--prospective longitudinal study in a multiethnic population.

BACKGROUND: Uncertainty exists regarding the optimal method to estimate glomerular filtration rate (GFR) for disease detection and monitoring. Widely used GFR estimates have not been validated in British ethnic minority populations. METHODS/DESIGN: Iohexol measured GFR will be the reference against which each estimating equation will be compared. The estimating equations will be based upon serum creatinine and/or cystatin C. The eGFR-C study has 5 components: 1) A prospective longitudinal cohort study of 1300 adults with stage 3 chronic kidney disease followed for 3 years with reference (measured) GFR and test (estimated GFR [eGFR] and urinary albumin-to-creatinine ratio) measurements at baseline and 3 years. Test measurements will also be undertaken every 6 months. The study population will include a representative sample of South-Asians and African-Caribbeans. People with diabetes and proteinuria (ACR ≥30 mg/mmol) will comprise 20-30% of the study cohort.2) A sub-study of patterns of disease progression of 375 people (125 each of Caucasian, Asian and African-Caribbean origin; in each case containing subjects at high and low risk of renal progression). Additional reference GFR measurements will be undertaken after 1 and 2 years to enable a model of disease progression and error to be built.3) A biological variability study to establish reference change values for reference and test measures.4) A modelling study of the performance of monitoring strategies on detecting progression, utilising estimates of accuracy, patterns of disease progression and estimates of measurement error from studies 1), 2) and 3).5) A comprehensive cost database for each diagnostic approach will be developed to enable cost-effectiveness modelling of the optimal strategy.The performance of the estimating equations will be evaluated by assessing bias, precision and accuracy. Data will be modelled as a linear function of time utilising all available (maximum 7) time points compared with the difference between baseline and final reference values. The percentage of participants demonstrating large error with the respective estimating equations will be compared. Predictive value of GFR estimates and albumin-to-creatinine ratio will be compared amongst subjects that do or do not show progressive kidney function decline. DISCUSSION: The eGFR-C study will provide evidence to inform the optimal GFR estimate to be used in clinical practice. TRIAL REGISTRATION: ISRCTN42955626.

Cost-Effectiveness of Plasma Microbial Cell-Free DNA Sequencing When Added to Usual Care Diagnostic Testing for Immunocompromised Host Pneumonia.

INTRODUCTION: Immunocompromised host pneumonia (ICHP) is an important cause of morbidity and mortality, yet usual care (UC) diagnostic tests often fail to identify an infectious etiology. A US-based, multicenter study (PICKUP) among ICHP patients with hematological malignancies, including hematological cell transplant recipients, showed that plasma microbial cell-free DNA (mcfDNA) sequencing provided significant additive diagnostic value. AIM: The objective of this study was to perform a cost-effectiveness analysis (CEA) of adding mcfDNA sequencing to UC diagnostic testing for hospitalized ICHP patients. METHODS: A semi-Markov model was utilized from the US third-party payer's perspective such that only direct costs were included, using a lifetime time horizon with discount rates of 3% for costs and benefits. Three comparators were considered: (1) All UC, which included non-invasive (NI) and invasive testing and early bronchoscopy; (2) All UC & mcfDNA; and (3) NI UC & mcfDNA & conditional UC Bronch (later bronchoscopy if the initial tests are negative). The model considered whether a probable causative infectious etiology was identified and if the patient received appropriate antimicrobial treatment through expert adjudication, and if the patient died in-hospital. The primary endpoints were total costs, life-years (LYs), equal value life-years (evLYs), quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio per QALY. Extensive scenario and probabilistic sensitivity analyses (PSA) were conducted. RESULTS: At a price of $2000 (2023 USD) for the plasma mcfDNA, All UC & mcfDNA was more costly ($165,247 vs $153,642) but more effective (13.39 vs 12.47 LYs gained; 10.20 vs 9.42 evLYs gained; 10.11 vs 9.42 QALYs gained) compared to All UC alone, giving a cost/QALY of $16,761. NI UC & mcfDNA & conditional UC Bronch was also more costly ($162,655 vs $153,642) and more effective (13.19 vs 12.47 LYs gained; 9.96 vs 9.42 evLYs gained; 9.96 vs 9.42 QALYs gained) compared to All UC alone, with a cost/QALY of $16,729. The PSA showed that above a willingness-to-pay threshold of $50,000/QALY, All UC & mcfDNA was the preferred scenario on cost-effectiveness grounds (as it provides the most QALYs gained). Further scenario analyses found that All UC & mcfDNA always improved patient outcomes but was not cost saving, even when the price of mcfDNA was set to $0. CONCLUSIONS: Based on the evidence available at the time of this analysis, this CEA suggests that mcfDNA may be cost-effective when added to All UC, as well as in a scenario using conditional bronchoscopy when NI testing fails to identify a probable infectious etiology for ICHP. Adding mcfDNA testing to UC diagnostic testing should allow more patients to receive appropriate therapy earlier and improve patient outcomes.

Internally sensed optical phased array.

Extending phased array techniques to optical frequencies is challenging because of the considerably smaller wavelengths and the difficulty of stabilizing the optical path lengths of multiple emitters to this level of precision. This is especially true under real-world conditions where thermal and vibrational disturbances cause path length variations that are considerable in relation to the wavelength. Earlier attempts have relied on an external mechanism to sense and compensate for any unwanted variations in the outgoing beams. Here we propose and demonstrate a method that does not rely on any external components. The method combines a pseudo-random noise phase modulation scheme together with conventional heterodyne interferometry to simultaneously measure phase variations between emitters. This information is then used to control the relative phases between the emitters and compensate for any unwanted disturbance. Experimental results are presented that support the viability of this design.

Exploring the approach to parameter uncertainty in early economic evaluations of surgical technology - a systematic review.

INTRODUCTION: The role of early economic evaluation (EEE) in the development of medical technology has been increasingly recognized; however, data on the use of EEE in surgical technology are sparse. The objective of this review was to explore the use of EEE in the development of surgical technologies, with emphasis on how uncertainty has been addressed. AREAS COVERED: A systematic review was conducted, and original articles employing any form of EEE of surgical technology were selected for review, with 10 studies included in the analysis. These studies demonstrated significant variation in the approach to managing parameter uncertainty, specifically regarding the type of analysis used and the inclusion of effectiveness parameters in sensitivity analysis. The conclusions drawn did not appear to factor in uncertainty in the models. EXPERT OPINION: Approaches to handling parameter uncertainty in previous EEEs of surgical technology have been limited, with some studies failing to address parameter uncertainty. In addition, EEEs do not appear to follow established guidelines with respect to the use of sensitivity analyses. It is important that EEEs of surgical technology address parameter uncertainty in order to draw more robust conclusions from the analysis and allow investors to consider this uncertainty when making investment decisions.

Perceptions and Attitudes Regarding Medical Device Development in Canada Among Canadian Innovators: A Qualitative Study.

OBJECTIVES: The Canadian medical device industry presents unique challenges to innovators. However, little attention has been paid to exploring the distinct experience of Canadian medical device innovators in the literature. The objective of this study is to explore the experience of Canadian innovators in navigating this industry, with a focus on their perceptions and attitudes towards the use of health economic evaluation. METHODS: Semi-structured interviews were conducted using virtual conferencing technology. All participants were C-level employees of small- and medium-sized enterprises (SMEs) with adequate knowledge of their company's overall strategy. Qualitative data were analyzed to reveal emerging themes. RESULTS: Interviews were performed with ten participants. Forty percent of participants rated themselves as having either minimal or basic knowledge of health economics. Thirty percent of participants had not pursued early economic evaluation of their device, while 90% rated health economics as being either "Quite important" or "Very important" to their company. The perception of increased barriers to successful device adoption in Canada relative to the USA was a prominent sentiment among participants, with 50% expressing discontentment with either the device approval process or health technology assessment process in Canada. Twenty percent stated that their primary target market involved the USA and/or other international jurisdictions. CONCLUSION: Canadian medical device innovators appear to understand the importance of health economic evaluation in the innovation process. However, they report difficulty with device approval and adoption, with some innovators focusing their efforts outside of Canada altogether. Further research should be directed toward understanding how to better support SMEs, given that they are a tremendous source of growth for the Canadian medical device industry.

Digitally enhanced homodyne interferometry.

We present two variations of a novel interferometry technique capable of simultaneously measuring multiple targets with high sensitivity. The technique performs a homodyne phase measurement by application of a four point phase shifting algorithm, with pseudo-random switching between points to allow multiplexed measurement based upon propagation delay alone. By multiplexing measurements and shifting complexity into signal processing, both variants realise significant complexity reductions over comparable methods. The first variant performs a typical coherent detection with a dedicated reference field and achieves a displacement noise floor 0.8 pm/√Hz above 50 Hz. The second allows for removal of the dedicated reference, resulting in further simplifications and improved low frequency performance with a 1 pm/√Hz noise floor measured down to 20 Hz. These results represent the most sensitive measurement performed using this style of interferometry whilst simultaneously reducing the electro-optic footprint.

Early Economic Evaluation to Identify the Necessary Test Characteristics of a New Typhoid Test to be Cost Effective in Ghana.

BACKGROUND: In Ghana, there are issues with the diagnosis of typhoid fever; these include delays in diagnosis, concerns about the accuracy of current tests, and lack of availability. These issues highlight the need for the development of a rapid, accurate, and easily accessible diagnostic test. The aim of this study was to conduct an early economic analysis of a hypothetical rapid test for typhoid fever diagnosis in Ghana and identify the necessary characteristics of the test for it to be cost effective in Ghana. METHODS: An early cost-utility analysis was conducted using a decision tree parameterized with secondary data sources, with reasonable assumptions made for unknown parameters. The patient population considered is individuals presenting with symptoms suggestive of typhoid fever at a healthcare facility in Ghana; a time horizon of 180 days and the Ghanaian national health service perspective were adopted for the analysis. Extensive sensitivity analysis was undertaken, including headroom analysis. RESULTS: The results here show that for a hypothetical test to perform better than the existing test (Widal) in terms of QALYs gained and cost effectiveness, it is necessary for it to have a high specificity (at least 70%) and should not be priced more than US$4. The overall value of conducting research to reduce uncertainty (over 5 years) is US$3287. CONCLUSION: The analysis shows the potential for the hypothetical test to replace the Widal test and the market potential of developing a new test in the Ghanaian setting.