Photon counting fibre optic distributed temperature sensing with a CMOS SPAD array.

Time-resolved fibre optic Raman distributed temperature sensing (DTS) measurements experience long measurement times due to a weak backscattered Raman signal inside optical fibres or limited detector count rates. Here, improvements to previous work based on individual detectors are demonstrated using a 512 pixel complementary-metal-oxide semiconductor (CMOS) single-photon avalanche diode (SPAD) line sensor array with integrated (on-chip) timing electronics. Multiplexed single photon counting increases count rate and decreases measurement time for practical applications. This allows temperature to be measured every 0.5 m with 0.7 °C accuracy and a 10 s measurement time using a 13.0 m optical fibre, performance over longer distance is also investigated.

High resolution TCSPC imaging of diffuse light with a one-dimensional SPAD array scanning system.

We report a time-correlated single-photon counting (TCSPC) imaging system based on a line-scanning architecture. The system benefits from the high fill-factor, active area, and large dimension of an advanced CMOS single-photon avalanche diode (SPAD) array line-sensor. A two-dimensional image is constructed using a moving mirror to scan the line-sensor field-of-view (FOV) across the target, to enable the efficient acquisition of a two-dimensional 0.26 Mpixel TCSPC image. We demonstrate the capabilities of the system for TCSPC imaging and locating objects obscured in scattering media - specifically to locate a series of discrete point sources of light along an optical fibre submerged in a highly scattering solution. We demonstrate that by selectively imaging using early arriving photons which have undergone less scattering than later arriving photons, our TCSPC imaging system is able to locate the position of discrete point sources of light than a non-time-resolved imaging system.

Measurement of Lepton-Jet Correlation in Deep-Inelastic Scattering with the H1 Detector Using Machine Learning for Unfolding.

The first measurement of lepton-jet momentum imbalance and azimuthal correlation in lepton-proton scattering at high momentum transfer is presented. These data, taken with the H1 detector at HERA, are corrected for detector effects using an unbinned machine learning algorithm (multifold), which considers eight observables simultaneously in this first application. The unfolded cross sections are compared with calculations performed within the context of collinear or transverse-momentum-dependent factorization in quantum chromodynamics as well as Monte Carlo event generators.

Time-resolved spectral-domain optical coherence tomography with CMOS SPAD sensors.

We present a first spectral-domain optical coherence tomography (SD-OCT) system deploying a complementary metal-oxide-semiconductor (CMOS) single-photon avalanche diode (SPAD) based, time-resolved line sensor. The sensor with 1024 pixels achieves a sensitivity of 87 dB at an A-scan rate of 1 kHz using a supercontinuum laser source with a repetition rate of 20 MHz, 38 nm bandwidth, and 2 mW power at 850 nm centre wavelength. In the time-resolved mode of the sensor, the system combines low-coherence interferometry (LCI) and massively parallel time-resolved single-photon counting to control the detection of interference spectra on the single-photon level based on the time-of-arrival of photons. For proof of concept demonstration of the combined detection scheme we show the acquisition of time-resolved interference spectra and the reconstruction of OCT images from selected time bins. Then, we exemplify the temporal discrimination feature with 50 ps time resolution and 249 ps timing uncertainty by removing unwanted reflections from along the optical path at a 30 mm distance from the sample. The current limitations of the proposed technique in terms of sensor parameters are analysed and potential improvements are identified for advanced photonic applications.

Adaptive treatment and robust control.

A control theory perspective on determination of optimal dynamic treatment regimes is considered. The aim is to adapt statistical methodology that has been developed for medical or other biostatistical applications to incorporate powerful control techniques that have been designed for engineering or other technological problems. Data tend to be sparse and noisy in the biostatistical area and interest has tended to be in statistical inference for treatment effects. In engineering fields, experimental data can be more easily obtained and reproduced and interest is more often in performance and stability of proposed controllers rather than modeling and inference per se. We propose that modeling and estimation should be based on standard statistical techniques but subsequent treatment policy should be obtained from robust control. To bring focus, we concentrate on A-learning methodology as developed in the biostatistical literature and H∞ -synthesis from control theory. Simulations and two applications demonstrate robustness of the H∞ strategy compared to standard A-learning in the presence of model misspecification or measurement error.

The Impact of Late Luteinizing Hormone-Releasing Hormone Agonist Dosing on Testosterone Suppression in Patients with Prostate Cancer: An Analysis of United States Clinical Data.

PURPOSE: We evaluated the timeliness of androgen deprivation therapy dosing, the impact of dosing nonadherence on testosterone, and the frequency of testosterone and prostate specific antigen testing in patients with prostate cancer. MATERIALS AND METHODS: We retrospectively analyzed the records of 22,860 patients with prostate cancer treated with luteinizing hormone-releasing hormone agonists. Analyses were done using 2 definitions of month, including a 28-day month (late dosing after day 28, 84, 112 or 168) and an extended month (late after day 32, 97, 128 or 194) for 1, 3, 4 and 6-month formulations, respectively. The prevalence of late dosing, associated testosterone values, and the frequency of testosterone and prostate specific antigen testing were assessed. Statistical significance was assessed with the unpaired t-test. RESULTS: Of the injections 84% and 27% were late for the 28-day and extended month analyses, respectively. For the 28-day month 60% and 29% of injections were late by more than 1 and more than 2 weeks, respectively. Of testosterone values 4% were greater than 50 ng/dl for early/on time injections using both definitions, and 15% and 27% were greater than 50 ng/dl when late, and for the 28-day month and the extended month, respectively. For early/on time vs late injections 22% vs 31% of testosterone values were greater than 20 ng/dl for the 28-day month and 21% vs 43% for the extended month. Mean testosterone was higher when late (49 ng/dl for 28-day month, 79 ng/dl for extended month) vs early/on time (both 21 ng/dl). Of the injections prostate specific antigen measurements were performed in 83% and testosterone assessment was done in only 13%. CONCLUSIONS: Luteinizing hormone-releasing hormone agonists were frequently (84%) administered later than the schedules used in pivotal trials. Nearly half of the late testosterone values for the extended month were greater than 20 ng/dl and mean testosterone was almost double the castration level. Elevated testosterone remained unidentified with infrequent testing.

Direct integration of micro-LEDs and a SPAD detector on a silicon CMOS chip for data communications and time-of-flight ranging.

We present integration of singulated micron-sized light emitting diodes (micro-LEDs) directly onto a silicon CMOS drive chip using a transfer printing method. An 8x8 micro-LED device array with individual control over each pixel is demonstrated with modulation bandwidths up to 50 MHz, limited by the large modulation depth of the driver chip. The 2 kHz frame rate CMOS driver also incorporates a Single Photon Avalanche Diode device thus allowing detection and transmission functionality on a single integrated chip. Visible light communications at data rates up to 1 Mbps, and time-of-flight ranging with cm-scale resolution are demonstrated using this hybrid integrated system.

Preequilibrium Asymmetries in the

The physical properties of neutrons emitted from neutron-induced fission are fundamental to our understanding of nuclear fission. However, while state-of-the-art fission models still incorporate isotropic fission neutron spectra, it is believed that the preequilibrium prefission component of these spectra is strongly anisotropic. The lack of experimental guidance on this feature has not motivated incorporation of anisotropic neutron spectra in fission models, though any significant anisotropy would impact descriptions of a fissioning system. In the present work, an excess of counts at high energies in the fission neutron spectrum of ^{239}Pu is clearly observed and identified as an excess of the preequilibrium prefission distribution above the postfission neutron spectrum. This excess is separated from the underlying postfission neutron spectrum, and its angular distribution is determined as a function in incident neutron energy and outgoing neutron detection angle. Comparison with neutron scattering models provides the first experimental evidence that the preequilibrium angular distribution is uncorrelated with the fission axis. The results presented here also impact the interpretation of several influential prompt fission neutron spectrum measurements.

Elevated fibrinogen, von Willebrand factor, and Factor VIII confer resistance to dilutional coagulopathy and activated protein C in normal pregnant women.

BACKGROUND: Gestational changes in coagulation factor concentrations include elevations in fibrinogen, Factor VIII, and von Willebrand factor (vWF). We hypothesised that blood samples from term pregnant (TP) subjects are less prone to coagulation disturbances from haemodilution compared with those from non-pregnant (NP) females. METHODS: Blood samples were collected from 15 NP and 15 TP subjects. In vitro haemodilution with normal saline was assessed by modified Clauss fibrinogen assay, factor activity, flow-chamber assay, and thromboelastometry. The impact of human fibrinogen concentrate (hFC), cryoprecipitate, and vWF/Factor VIII (FVIII) concentrate replacement in diluted TP and NP blood was compared. Thrombin generation and activated protein C sensitivity were assessed. RESULTS: TP blood contained twice the concentrations of fibrinogen, FVIII, and vWF relative to NP blood (P<0.0001). Platelet thrombus formation (PTF) under flow was reduced by 99.2% and 69.2% in diluted NP and TP blood, respectively. Platelet thrombus formation was partially restored by adding vWF/FVIII, but not hFC or cryoprecipitate. Fibrin clot firmness approached the threshold of 10 mm in diluted NP blood, and clot firmness was effectively restored by hFC, but not by vWF/FVIII. In the presence of thrombomodulin, peak thrombin generation was decreased by 86.7% in NP plasma, but by 31.8% in TP plasma (P<0.0001 vs NP plasma), indicating reduced activated protein C sensitivity in TP plasma. Both elevated FVIII and haemodilution contributed to activated protein C insensitivity. CONCLUSIONS: Our in vitro model showed relative resistance of TP blood to dilutional coagulation changes with respect to platelet adhesion, fibrin polymerisation, and thrombin generation. Careful therapeutic monitoring for different pro-haemostatic agents in pregnant women is warranted.

First nations people's perspectives on barriers and supports for enhancing HPV vaccination: Foundations for sustainable, community-driven strategies.

OBJECTIVE: In Canada, Indigenous people have higher human papillomavirus (HPV) infection rates, lower screening rates for cervical cancer, and higher rates of invasive cancer, leading to worse cervical cancer-related outcomes than observed in non-Indigenous Canadian women. Lingering harms from European colonization drive these health inequities and create public health challenges. Policy guidance is needed to optimize HPV vaccination rates and, thereby, decrease the burden of HPV-related illness, including high-morbidity surgical procedures and chemo-radiotherapy. The Enhancing HPV Vaccination In First Nations Populations in Alberta (EHVINA) project focuses on First Nations, a diverse subset of recognized Indigenous people in Canada, and seeks to increase HPV vaccination among girls and boys living in First Nation communities. METHODS: Developing an effective strategy requires partnership with affected communities to better understand knowledge and perceptions about cancer, healthcare, and the HPV vaccine. A 2017 community gathering was convened to engage First Nations community members, health directors, and health services researchers in dialogue around unique barriers and supports to HPV vaccination in Alberta. Voices of community Elders, parents, health directors, and cancer survivors (n=24) are presented as qualitative evidence to help inform intervention design. RESULTS: Key findings from discussions indicate barriers to HPV vaccination include resource constraints and service infrastructure gaps, historical mistrust in healthcare systems, impacts of changing modes of communication, and community sensitivities regarding sexual health promotion. Supports were identified as strengthened inter-generational relationships in communities. CONCLUSIONS AND FUTURE DIRECTION: Ongoing dialogue and co-development of community-based strategies to increase HPV vaccine uptake are required. The identification of possible barriers to HPV vaccination in a Canadian Indigenous population contributes to limited global literature on this subject and may inform researchers and policy makers who work with Indigenous populations in other regions.

Factor IX from prothrombin complex concentrate augments low dose tissue factor-triggered thrombin generation in vitro.

BACKGROUND: Prothrombin complex concentrate (PCC) is increasingly used to correct acquired coagulopathy in trauma and surgery. Dosing of PCC is guided by the prothrombin time, which only reflects the onset of thrombin generation, but does not account for variations in intrinsic pathway coagulation factors, including factor IX (FIX). We hypothesised that FIX contained in PCC could strongly influence thrombin generation patterns. METHODS: Pooled normal, FIX-deficient, and warfarinised plasma were used to analyse the effects of FIX contained in PCC. PCC was evaluated at final concentrations of 0.2 and 0.4 IU ml-1 in FIX-deficient and normal plasma, and at 0.6 IU ml-1 in warfarinised plasma with elevated FVIII (1.5 IU ml-1), 40% dilution with saline, or both. The effects on thrombin generation were assessed by measuring both procoagulant and inhibitory segments. RESULTS: FIX-deficient plasma had lower peak thrombin generation [30.6 (20.5-35.8) nM vs 130.2 (107-168) nM] and endogenous thrombin potential [472 (391-532) nM vs 1096 (958-1190) nM] than normal plasma. PCC addition resulted in significant increases of peak thrombin generation [81.8 (37.3-98.3) nM] and endogenous thrombin potential [808 (472-842) nM] in FIX-deficient plasma. The combination of FVIII and PCC resulted in greater increases relative to each agent alone, restoring normal thrombin generation. After 40% dilution, adding PCC, FVIII, or both, to FIX-deficient plasma increased peak thrombin generation, and prolonged the inhibitory phase of the endogenous thrombin potential. CONCLUSIONS: FIX derived from PCC strongly enhances tissue factor-triggered thrombin generation in the presence of elevated FVIII activity. Haemodilution further enhances procoagulant effects of FIX and FVIII by slowing down inhibition of procoagulant enzymes. Dosing of PCC per prothrombin time may underestimate PCC's procoagulant potential because it does not account for intrinsic tenase or antithrombin activity.

Periarticular Ropivacaine Cocktail Is Equivalent to Liposomal Bupivacaine Cocktail in Bilateral Total Knee Arthroplasty.

BACKGROUND: This study compares the effectiveness of 2 commonly used periarticular injection formulations: liposomal bupivacaine and bupivacaine (EXP) and ropivacaine, epinephrine, ketorolac, and clonidine (ROP) in patients undergoing bilateral total knee arthroplasty or unicompartmental knee arthroplasty. METHODS: Twenty-six total knee arthroplasty patients (52 knees) and 3 unicompartmental knee arthroplasty patients (6 knees) undergoing simultaneous, bilateral arthroplasty were randomized to receive periarticular injections in a blinded fashion. Even birth year patients were selected for PAI of EXP in the right knee and ROP in the left knee. This was reversed for odd birth years. Visual analog scale pain scores for each knee and patient perceived difference in knee functional recovery were recorded during physical therapy, throughout the hospitalization. RESULTS: There was no difference in visual analog scale pain scores between the EXP and ROP injected knees at any time point during the first 2 days after surgery. Postoperative pain scores averaged 41.9 mm (range 0-100 mm) for EXP and 43.1 mm (range 0-100 mm) for ROP. Patients were unable to detect a difference in the functional recovery between their knees on postoperative day 0, 1, or 2. No complications as a result of either periarticular injection occurred. CONCLUSION: Periarticular injections of EXP and ROP are equally effective after knee arthroplasty and patients do not appreciate differences between knees as determined by pain score or perceived functional recovery during the first 2 days after bilateral knee arthroplasty. This study demonstrates that a liposomal bupivacaine injection does not add an incremental benefit for pain control compared to a less expensive injection formulation.

A combined tract-based spatial statistics and voxel-based morphometry study of the first MRI scan after diagnosis of amyotrophic lateral sclerosis with subgroup analysis.

BACKGROUND AND PURPOSE: This study aims to compare the cortical and subcortical deep gray matter (GM) and white matter (WM) of ALS subjects and controls and to compare ALS subjects with (ALScog) and without (ALSnon-cog) cognitive impairment. MATERIALS AND METHODS: The study was performed in 30 ALS subjects, and 19 healthy controls. Structural T1- and diffusion-weighted MRI data were analyzed using voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS). RESULTS: All DTI measures and GM volume differed significantly between ALS subjects and controls. Compared to controls, greater DTI changes were present in ALScog than ALSnon-cog subjects. GM results showed reduction in the caudate nucleus volume in ALScog subjects compared to ALSnon-cog. and comparing all ALS with controls, there were changes on the right side and in a small region in the left middle frontal gyrus. CONCLUSION: This combined DTI and VBM study showed changes in motor and extra-motor regions. The DTI changes were more extensive in ALScog than ALSnon-cog subjects. It is likely that the inclusion of ALS subjects with cognitive impairment in previous studies resulted in extra-motor WM abnormalities being reported in ALS subjects.

pH sensing through a single optical fibre using SERS and CMOS SPAD line arrays.

Full exploitation of fibre Raman probes has been limited by the obstruction of weak Raman signals by background fluorescence of the sample and the intrinsic Raman signal of the delivery fibre. Here we utilised functionalised gold nanoshells (NS) to take advantage of the surface-enhanced Raman spectroscopy (SERS) effect to enhance the pH responsive spectrum of 4-mercaptobenzoic acid (MBA). However, the fibre background is still dominant. Using the photon arrival time-resolving capability of a CMOS single-photon avalanche diode (SPAD) based line sensor, we recover the SERS spectrum without a fibre background in a 10 s measurement. In this manner, pH sensing through a multimode fibre at a low excitation power that is safe for future in vivo applications, with short acquisition times (10 or 60 s), is demonstrated. A measurement precision of ± 0.07 pH units is thus achieved.

Time-resolved spectroscopy at 19,000 lines per second using a CMOS SPAD line array enables advanced biophotonics applications.

A SPAD-based line sensor fabricated in 130 nm CMOS technology capable of acquiring time-resolved fluorescence spectra (TRFS) in 8.3 milliseconds is presented. To the best of our knowledge, this is the fastest time correlated single photon counting (TCSPC) TRFS acquisition reported to date. The line sensor is an upgrade to our prior work and incorporates: i) parallelized interface from sensor to surrounding circuitry enabling high line rate to the PC (19,000 lines/s) and ii) novel time-gating architecture where detected photons in the OFF region are rejected digitally after the output stage of the SPAD. The time-gating architecture was chosen to avoid electrical transients on the SPAD high voltage supplies when gating is achieved by excess bias modulation. The time-gate has an adjustable location and time window width allowing the user to focus on time-events of interest. On-chip integrated center-of-mass (CMM) calculations provide efficient acquisition of photon arrivals and direct lifetime estimation of fluorescence decays. Furthermore, any of the SPC, TCSPC and on-chip CMM modes can be used in conjunction with the time-gating. The higher readout rate and versatile architecture greatly empower the user and will allow widespread applications across many techniques and disciplines. Here we focused on 3 examples of TRFS and time-gated Raman spectroscopy: i) kinetics of chlorophyll A fluorescence from an intact leaf; ii) kinetics of a thrombin biosensor FRET probe from quenched to fluorescence states; iii) ex vivo mouse lung tissue autofluorescence TRFS; iv) time-gated Raman spectroscopy of toluene at 3056 cm-1 peak. To the best of our knowledge, we detect spectrally for the first time the fast rise in fluorescence lifetime of chlorophyll A in a measurement over single fluorescent transient.