Ultrabroadband flying-focus using an axiparabola-echelon pair.

Flying-focus pulses promise to revolutionize laser-driven secondary sources by decoupling the trajectory of the peak intensity from the native group velocity of the medium over distances much longer than a Rayleigh range. Previous demonstrations of the flying focus have either produced an uncontrolled trajectory or a trajectory that is engineered using chromatic methods that limit the duration of the peak intensity to picosecond scales. Here we demonstrate a controllable ultrabroadband flying focus using a nearly achromatic axiparabola-echelon pair. Spectral interferometry using an ultrabroadband superluminescent diode was used to measure designed super- and subluminal flying-focus trajectories and the effective temporal pulse duration as inferred from the measured spectral phase. The measurements demonstrate that a nearly transform- and diffraction-limited moving focus can be created over a centimeter-scale-an extended focal region more than 50 Rayleigh ranges in length. This ultrabroadband flying-focus and the novel axiparabola-echelon configuration used to produce it are ideally suited for applications and scalable to >100 TW peak powers.

Does gabapentin provide benefit for patients with knee OA? A benefit-harm and cost-effectiveness analysis.

OBJECTIVE: Gabapentin can treat neuropathic pain syndromes and has increasingly been prescribed to treat nociplastic pain. Some patients with knee osteoarthritis (OA) suffer from both nociceptive and nociplastic pain. We examined the cost-effectiveness of adding gabapentin to knee OA care. METHOD: We used the Osteoarthritis Policy Model, a validated Monte Carlo simulation of knee OA, to examine the value of gabapentin in treating knee OA by comparing three strategies: 1) usual care, gabapentin sparing (UC-GS); 2) targeted gabapentin (TG), which provides gabapentin plus usual care for those who screen positive for nociplastic pain on the modified PainDETECT questionnaire (mPD-Q) and usual care only for those who screen negative; and 3) universal gabapentin plus usual care (UG). Outcomes included cumulative quality-adjusted life years (QALYs), lifetime direct medical costs, and incremental cost-effectiveness ratios (ICERs), discounted at 3% annually. We derived model inputs from published literature and national databases and varied key input parameters in sensitivity analyses. RESULTS: UC-GS dominated both gabapentin-containing strategies, as it led to lower costs and more QALYs. TG resulted in a cost increase of $689 and a cumulative QALY reduction of 0.012 QALYs. UG resulted in a further $1,868 cost increase and 0.036 QALY decrease. The results were robust to plausible changes in input parameters. The lowest TG strategy ICER of $53,000/QALY was reported when mPD-Q specificity was increased to 100% and AE rate was reduced to 0%. CONCLUSION: Incorporating gabapentin into care for patients with knee OA does not appear to offer good value.

Inverse Bremsstrahlung Absorption.

Inverse bremsstrahlung absorption was measured based on transmission through a finite-length plasma that was thoroughly characterized using spatially resolved Thomson scattering. Expected absorption was then calculated using the diagnosed plasma conditions while varying the absorption model components. To match data, it is necessary to account for (i) the Langdon effect; (ii) laser-frequency (rather than plasma-frequency) dependence in the Coulomb logarithm, as is typical of bremsstrahlung theories but not transport theories; and (iii) a correction due to ion screening. Radiation-hydrodynamic simulations of inertial confinement fusion implosions have to date used a Coulomb logarithm from the transport literature and no screening correction. We anticipate that updating the model for collisional absorption will substantially revise our understanding of laser-target coupling for such implosions.

Vulnerable newborn types: analysis of subnational, population-based birth cohorts for 541 285 live births in 23 countries, 2000-2021.

OBJECTIVE: To examine prevalence of novel newborn types among 541 285 live births in 23 countries from 2000 to 2021. DESIGN: Descriptive multi-country secondary data analysis. SETTING: Subnational, population-based birth cohort studies (n = 45) in 23 low- and middle-income countries (LMICs) spanning 2000-2021. POPULATION: Liveborn infants. METHODS: Subnational, population-based studies with high-quality birth outcome data from LMICs were invited to join the Vulnerable Newborn Measurement Collaboration. We defined distinct newborn types using gestational age (preterm [PT], term [T]), birthweight for gestational age using INTERGROWTH-21st standards (small for gestational age [SGA], appropriate for gestational age [AGA] or large for gestational age [LGA]), and birthweight (low birthweight, LBW [<2500 g], nonLBW) as ten types (using all three outcomes), six types (by excluding the birthweight categorisation), and four types (by collapsing the AGA and LGA categories). We defined small types as those with at least one classification of LBW, PT or SGA. We presented study characteristics, participant characteristics, data missingness, and prevalence of newborn types by region and study. RESULTS: Among 541 285 live births, 476 939 (88.1%) had non-missing and plausible values for gestational age, birthweight and sex required to construct the newborn types. The median prevalences of ten types across studies were T+AGA+nonLBW (58.0%), T+LGA+nonLBW (3.3%), T+AGA+LBW (0.5%), T+SGA+nonLBW (14.2%), T+SGA+LBW (7.1%), PT+LGA+nonLBW (1.6%), PT+LGA+LBW (0.2%), PT+AGA+nonLBW (3.7%), PT+AGA+LBW (3.6%) and PT+SGA+LBW (1.0%). The median prevalence of small types (six types, 37.6%) varied across studies and within regions and was higher in Southern Asia (52.4%) than in Sub-Saharan Africa (34.9%). CONCLUSIONS: Further investigation is needed to describe the mortality risks associated with newborn types and understand the implications of this framework for local targeting of interventions to prevent adverse pregnancy outcomes in LMICs.

The burden of OA-health services and economics.

Osteoarthritis (OA) is a highly prevalent and disabling condition that affects over 7% of people globally (528 million people). Prevalence levels are even higher in countries with established market economies, which have older demographic profiles and a higher prevalence of obesity, such as the US (14%). As the 15th highest cause of years lived with disability (YLDs) worldwide, the burden OA poses to individuals is substantial, characterized by pain, activity limitations, and reduced quality of life. The economic impact of OA, which includes direct and indirect (time) costs, is also substantial, ranging from 1 to 2.5% of gross national product (GNP) in countries with established market economies. In regions around the world, the average annual cost of OA for an individual is estimated between $700-$15,600 (2019 USD). Though trends in OA prevalence vary by geography, the prevalence of OA is projected to rise in regions with established market economies such as North America and Europe, where populations are aging and the prevalence of obesity is rising.

Quantitative sensory testing: identifying pain characteristics in patients with osteoarthritis.

OBJECTIVE: This review outlines the most commonly used quantitative sensory tests to identify pain sensitization. We examine cross-sectional associations between quantitative sensory testing (QST) measures and OA symptoms and severity, along with longitudinal associations between QST findings and response to surgical and non-surgical treatments for OA. DESIGN: We conducted a search in PubMed for English language papers including 'osteoarthritis' and 'quantitative sensory testing' as search terms. Papers that did not pertain specifically to OA or QST were excluded. RESULTS: Pressure Pain Threshold (PPT), Conditioned Pain Modulation (CPM), and Temporal Summation (TS) are the QST measures used most frequently to identify pain sensitization. Findings indicate that persons with knee OA often exhibit lower PPT thresholds, inefficient CPM, and facilitated TS as compared with controls who do not have OA, supporting the discriminant validity of QST. Pre-treatment QST has shown some success in identifying persons who experience less pain relief from surgical and non-surgical treatments for knee OA. Post-treatment QST has shown that sometimes PPT and CPM can normalize (PPT thresholds increase, and CPM becomes efficient) in patients for whom joint replacement is successful. Recent studies indicate that QST measures are more closely associated with pain severity than OA radiographic severity, suggesting that sensitization may be a trait rather than a state. CONCLUSIONS: QST may have a role in identifying persons who are susceptible to chronic pain and may offer an opportunity for personalized, more effective treatment of OA.

Mechanical symptoms and meniscal tear: a reappraisal.

OBJECTIVE: To identify and summarize literature related to the association between mechanical symptoms (catching and locking of the knee), the presence of meniscal tear, and outcomes after arthroscopic surgery. DESIGN: We searched PubMed and hand-searched reference lists for relevant articles and selected 38 for analysis. RESULTS: Mechanical symptoms appear to have modest sensitivity (ranging 0.32-0.69), specificity (ranging 0.45-0.74) and positive predictive value (ranging 0.75-0.81) for meniscal tear. There is also very little evidence to suggest that those with mechanical symptoms experience better outcomes after arthroscopic surgery. CONCLUSION: Our examination of the literature does not support the hypothesis that mechanical symptoms are related to the presence of meniscal tear or portend better outcomes after arthroscopic surgery.

Direct Measurement of the Return Current Instability in a Laser-Produced Plasma.

Measurements were made of the return current instability growth rate, demonstrating its concurrence with nonlocal transport. Thomson scattering was used to measure a maximum growth rate of 5.1×10^{9} Hz, which was 3 times less than classical Spitzer-Härm theory predicts. The measured plasma conditions indicate the heat flux was nonlocal, and Vlasov-Fokker-Planck simulations that account for nonlocality reproduce the measured growth rates. Furthermore, the threshold for the return current instability was measured (δ_{T}=0.017±0.002) to be in good agreement with previous theoretical models.

Increased odds ratio for erectile dysfunction in COVID-19 patients.

PURPOSE: Erectile dysfunction and COVID-19 share similar risk factors, including vascular disruption of integrity, cytokine release, cardiovascular disease, diabetes and obesity. The aim of this study was to investigate the association between erectile dysfunction and COVID-19 patients. METHODS: Odds ratio for erectile dysfunction in patients with a history of COVID-19 with and without comorbidities were calculated using a patients' registry platform i2b2. ICD-10 diagnoses codes were accessed for queries and data were analyzed using logistic regression. RESULTS: Patients with COVID-19 were 3.3 times more likely to have erectile dysfunction with 95% CI (2.8, 3.8). The association became stronger with odds ratio 4.8 (95% CI (4.1, 5.7)) after adjusting for age groups. The odds ratio remained the same after adjusting for smoking status with 3.5 (95% CI (3.0, 4.1)). After adjusting for race, COVID-19 patients were 2.6 (95% CI (2.2, 3.1)) times more likely to have erectile dysfunction. The odds ratio were 1.6, 1.8, 1.9 and 2.3 after adjusting for respiratory disease, obesity, circulatory disease and diabetes, respectively. CONCLUSION: COVID-19 and erectile dysfunction are strongly associated even after adjustment for known risk factors and demographics.

Unilateral diaphragmatic paresis following supracostal post-percutaneous nephrolithotomy.

Unilateral acquired diaphragmatic paresis is a known complication of thoracic surgeries. Direct mechanical injury to the phrenic nerve during surgery results in this complication. However its occurrence post-percutaneous nephrolithotomy (PCNL) has not been described. We report a 43-year-old man who underwent prone PCNL for endourological management of left complete staghorn calculus. Access via the 10th left intercostal space, under fluoroscopy, was carried out to remove the calculus. Post-operative, the routine chest radiograph revealed left hemidiaphragmatic blunting. Computerized tomography of the chest confirmed left hemidiaphragmatic elevation, suggesting unilateral diaphragmatic paresis. He did not have any respiratory symptoms, was managed conservatively with chest physiotherapy and incentive spirometry and responded extremely well. The absence of reported cases of diaphragmatic paresis post PCNL lends to a dearth in knowledge regarding recognition and management. This case report aims to acquaint urologists with this rare complication associated with supracostal PCNL and provide a rational management plan.

Cost-effectiveness of duloxetine for knee OA subjects: the role of pain severity.

OBJECTIVE: Establish the impact of pain severity on the cost-effectiveness of generic duloxetine for knee osteoarthritis (OA) in the United States. DESIGN: We used a validated computer simulation of knee OA to compare usual care (UC) - intra-articular injections, opioids, and total knee replacement (TKR) - to UC preceded by duloxetine in those no longer achieving pain relief from non-steroidal anti-inflammatory drugs (NSAIDs). Outcomes included quality-adjusted life years (QALYs), lifetime medical costs, and incremental cost-effectiveness ratios (ICERs). We considered cohorts with mean ages 57-75 years and Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain 25-55 (0-100, 100-worst). We derived inputs from published data. We discounted costs and benefits 3% annually. We conducted sensitivity analyses of duloxetine efficacy, duration of pain relief, toxicity, and costs. RESULTS: Among younger subjects with severe pain (WOMAC pain = 55), duloxetine led to an additional 9.6 QALYs per 1,000 subjects (ICER = $88,500/QALY). The likelihood of duloxetine being cost-effective at willingness-to-pay (WTP) thresholds of $50,000/QALY and $100,000/QALY was 40% and 54%. Offering duloxetine to older patients with severe pain led to ICERs >$150,000/QALY. Offering duloxetine to subjects with moderate pain (pain = 25) led to ICERs <$50,000/QALY, regardless of age. Among knee OA subjects with severe pain (pain = 55) who are unwilling or unable to undergo TKR, ICERs were <$50,600/QALY, regardless of age. CONCLUSIONS: Duloxetine is a cost-effective addition to knee OA UC for subjects with moderate pain or those with severe pain unable or unwilling to undergo TKR. Among younger subjects with severe pain, duloxetine is cost-effective at WTP thresholds >$88,500/QALY.

Nonuniform Absorption and Scattered Light in Direct-Drive Implosions Driven by Polarization Smoothing.

Laser-direct-drive symmetric implosions on OMEGA illuminate a target with 60 laser beams and are designed to produce spherical implosions. Each beam is smoothed using orthogonal polarizations obtained by passing the laser beams through distributed polarization rotators (DPRs). Observations of light scattered from OMEGA implosions do not show the expected symmetry and have much larger variation than standard predictions. For the first time, we have quantified the scattered-light nonuniformity from individual beams and identified the DPRs as the source of the enhanced nonuniformity. An instrument was invented that isolated and measured the variation in the intensity and polarization of the light scattered from each OMEGA beam. The asymmetric intensity and polarization measurements are explained when the on-target offsets between the two orthogonal polarizations produced by the DPRs are modeled using a 3D cross-beam energy transfer (CBET) code that tracks the polarizations of each beam. The time-integrated nonuniformity in laser absorption and scattered light due to CBET and the DPR polarization offsets during high-performance OMEGA implosions is predicted to be significant and dominated by low spherical harmonic mode numbers. The nonuniformity is predicted to be greatly reduced by replacing the DPRs with new optics that create smaller offsets.

Measurements of Non-Maxwellian Electron Distribution Functions and Their Effect on Laser Heating.

Electron velocity distribution functions driven by inverse bremsstrahlung heating are measured to be non-Maxwellian using a novel angularly resolved Thomson-scattering instrument and the corresponding reduction of electrons at slow velocities results in a ∼40% measured reduction in inverse bremsstrahlung absorption. The distribution functions are measured to be super-Gaussian in the bulk (v/v_{th}<3) and Maxwellian in the tail (v/v_{th}>3) when the laser heating rate dominates over the electron-electron thermalization rate. Simulations with the particle code quartz show the shape of the tail is dictated by the uniformity of the laser heating.

Cross-Beam Energy Transfer Saturation by Ion Heating.

We measure cross-beam energy transfer (CBET) saturation by ion heating in a gas-jet plasma characterized using Thomson scattering. A wavelength-tunable ultraviolet (UV) probe laser beam interacts with four intense UV pump beams to drive large-amplitude ion-acoustic waves. For the highest-intensity interactions, the power transfer to the probe laser drops, demonstrating ion-acoustic wave saturation. Over this time, the ion temperature is measured to increase by a factor of 7 during the 500-ps interaction. Particle-in-cell simulations show ion trapping and a subsequent ion heating consistent with measurements. Linear kinetic CBET models are found to agree well with the observed energy transfer when the measured plasma conditions are used.

Evaluation of a Hyperbaric Oxygen Therapy Intervention in Individuals with Fibromyalgia.

OBJECTIVE: To evaluate the feasibility and safety of hyperbaric oxygen therapy (HBOT) in patients with fibromyalgia (FM). DESIGN: A cohort study with a delayed treatment arm used as a comparator. SETTING: Hyperbaric Medicine Unit, Toronto General Hospital, Ontario, Canada. SUBJECTS: Eighteen patients diagnosed with FM according to the American College of Rheumatology and a score ≥60 on the Revised Fibromyalgia Impact Questionnaire. METHODS: Participants were randomized to receive immediate HBOT intervention (n = 9) or HBOT after a 12-week waiting period (n = 9). HBOT was delivered at 100% oxygen at 2.0 atmospheres per session, 5 days per week, for 8 weeks. Safety was evaluated by the frequency and severity of adverse effects reported by patients. Feasibility was assessed by recruitment, retention, and HBOT compliance rates. Both groups were assessed at baseline, after HBOT intervention, and at 3 months' follow-up. Validated assessment tools were used to evaluate pain, psychological variables, fatigue, and sleep quality. RESULTS: A total of 17 patients completed the study. One patient withdrew after randomization. HBOT-related adverse events included mild middle-ear barotrauma in three patients and new-onset myopia in four patients. The efficacy of HBOT was evident in most of the outcomes in both groups. This improvement was sustained at 3-month follow-up assessment. CONCLUSION: HBOT appears to be feasible and safe for individuals with FM. It is also associated with improved global functioning, reduced symptoms of anxiety and depression, and improved quality of sleep that was sustained at 3-month follow-up assessment.

Solvent-Assisted Hot Melt Extrusion of a Thermally Labile, High Melting Point Compound.

Molecular dispersions are a highly effective method of increasing bioavailability for a poorly soluble active pharmaceutical ingredient (API) and can be prepared on a large scale by hot melt extrusion (HME). Processing thermally labile active pharmaceutical ingredients (APIs) via HME is generally more difficult, with operating temperatures limited to below that of the API melting point. API melting is considered essential to facilitate the formation of a fully homogeneous amorphous system. Processing below the melting point renders the system much more susceptible to residual crystalline content; hence, HME is not suitable for APIs which degrade upon melting. In the following work, meloxicam (MEL) was used as a model API, possessing properties of high melting temperature and thermal lability. In this proof of concept work, a modified HME method, termed solvent-assisted HME, was used to overcome this issue and prepare an amorphous solid dispersion using HME, wherein a solvent was incorporated in the formulation blend during extrusion and removed post-processing. Formulations containing 10%wt meloxicam (MEL) and 90%wt polyvinylpyrrolidone vinyl acetate (PVPVA) copolymer were extruded using a twin-screw extruder at temperatures below the melting point of MEL. Dimethylformamide (DMF) solvent was added directly into the extruder barrel through a liquid addition port, resulting in extrudate products having a higher conversion of API to the amorphous form. The incorporation of solvent allowed a significant reduction in processing temperatures due to its increased mobility, while also driving the conversion of the API to its amorphous form. The solvent was successfully reduced through a secondary drying step using a vacuum oven. This advancement has demonstrated the potential for thermally labile APIs to be processed via HME expanding the applications of this technology.

Estimating contextual effect in nonpharmacological therapies for pain in knee osteoarthritis: a systematic analytic review.

OBJECTIVE: Conduct a systematic review and use meta-analytic techniques to estimate the proportion of total treatment effect that can be attributable to contextual effects (PCE) in adults receiving nonpharmacological, nonsurgical (NPNS) treatments for knee osteoarthritis (OA). DESIGN: We reviewed the published literature to identify five frequently studied NPNS treatments for knee OA: exercise, acupuncture, ultrasound, laser, and transcutaneous electrical nerve stimulation (TENS). We searched for randomized controlled trials (RCTs) of these treatments and abstracted pre- and post-intervention pain scores for groups receiving placebo and active treatments. For each study we calculated the PCE by dividing the change in pain in the placebo group by the change in pain in the active treatment group. We log transformed the PCE measure and pooled across studies using a random effects model. RESULTS: We identified 25 studies for analysis and clustered the RCTs into two groups: acupuncture and topical energy modalities (TEM). 13 acupuncture studies included 1,653 subjects and 12 TEM studies included 572 subjects. The combined PCE was 0.61 (95% CI 0.46-0.80) for acupuncture and 0.69 (95% CI 0.54-0.88) for TEM. CONCLUSION: Our findings suggest that about 61% and 69% of the total treatment effect experienced by subjects receiving acupuncture and TEM treatments, respectively, for knee OA pain may be explained by contextual effects. Contextual effects may include the placebo effect, changes attributable to natural history, and effects of co-therapies. These data highlight the important role of contextual effects in the response to NPNS OA treatments.

Long-term clinical and economic outcomes of a short-term physical activity program in knee osteoarthritis patients.

OBJECTIVE: Physical activity (PA) in the US knee osteoarthritis (OA) population is low, despite well-established health benefits. PA program implementation is often stymied by sustainability concerns. We sought to establish parameters that would make a short-term (3-year efficacy) PA program a cost-effective component of long-term OA care. METHOD: Using a validated computer microsimulation (Osteoarthritis Policy Model), we examined the long-term clinical (e.g., comorbidities averted), quality of life (QoL), and economic impacts of a 3-year PA program, based upon the SPARKS (Studying Physical Activity Rewards after Knee Surgery) Trial, for inactive knee OA patients. We determined the cost, efficacy, and impact of PA on QoL and medical costs that would make a PA program a cost-effective addition to OA care. RESULTS: Among the 14 million with knee OA in the US, >4 million are inactive. Participation of 10% in the modeled PA program could save 200 cases of cardiovascular disease, 400 cases of diabetes, and 6,800 quality-adjusted life-years (QALYs). The program had an incremental cost-effectiveness ratio (ICER) of $16,100/QALY. Tripling PA program cost ($860/year) raised the ICER to $108,300/QALY; varying QoL benefits from PA yielded ICERs of $8,800/QALY-$99,900/QALY; varying background cost savings from PA did not qualitatively impact ICERs. Offering the PA program to any adults with knee OA (not only inactive) yielded $31,000/QALY. CONCLUSION: A PA program with 3-year efficacy in the knee OA population carried favorable long-term clinical and economic benefits. These results offer justification for policymakers and payers considering a PA intervention incorporated into knee OA care.

Plasma Collision in a Gas Atmosphere.

We present a study on the impact of a gas atmosphere on the collision of two counterpropagating plasmas (gold and carbon). Imaging optical Thomson scattering data of the plasma collision with and without helium in between have been obtained at the Omega laser facility. Without gas, we observed large scale mixing of colliding gold and carbon ions. Once ambient helium is added, the two plasmas remain separated. The difference in ionic temperature is consistent with a reduction of the maximum Mach number of the flow from M=7 to M=4. It results in a reduction of a factor ∼10 of the counterstreaming ion-ion mean free path. By adding a low-density ambient gas, it is possible to control the collision of two high-velocity counterstreaming plasma, transitioning from an interpenetrating regime to a regime in agreement with a hydrodynamic description.

Measurement of Kinetic-Scale Current Filamentation Dynamics and Associated Magnetic Fields in Interpenetrating Plasmas.

We present the first local, quantitative measurements of ion current filamentation and magnetic field amplification in interpenetrating plasmas, characterizing the dynamics of the ion Weibel instability. The interaction of a pair of laser-generated, counterpropagating, collisionless, supersonic plasma flows is probed using optical Thomson scattering (TS). Analysis of the TS ion-feature revealed anticorrelated modulations in the density of the two ion streams at the spatial scale of the ion skin depth c/ω_{pi}=120 µm, and a correlated modulation in the plasma current. The inferred current profile implies a magnetic field amplitude ∼30±6 T, corresponding to ∼1% of the flow kinetic energy, indicating that magnetic trapping is the dominant saturation mechanism.