Nirmatrelvir for Vaccinated or Unvaccinated Adult Outpatients with Covid-19.

BACKGROUND: Nirmatrelvir in combination with ritonavir is an antiviral treatment for mild-to-moderate coronavirus disease 2019 (Covid-19). The efficacy of this treatment in patients who are at standard risk for severe Covid-19 or who are fully vaccinated and have at least one risk factor for severe Covid-19 has not been established. METHODS: In this phase 2-3 trial, we randomly assigned adults who had confirmed Covid-19 with symptom onset within the past 5 days in a 1:1 ratio to receive nirmatrelvir-ritonavir or placebo every 12 hours for 5 days. Patients who were fully vaccinated against Covid-19 and who had at least one risk factor for severe disease, as well as patients without such risk factors who had never been vaccinated against Covid-19 or had not been vaccinated within the previous year, were eligible for participation. Participants logged the presence and severity of prespecified Covid-19 signs and symptoms daily from day 1 through day 28. The primary end point was the time to sustained alleviation of all targeted Covid-19 signs and symptoms. Covid-19-related hospitalization and death from any cause were also assessed through day 28. RESULTS: Among the 1296 participants who underwent randomization and were included in the full analysis population, 1288 received at least one dose of nirmatrelvir-ritonavir (654 participants) or placebo (634 participants) and had at least one postbaseline visit. The median time to sustained alleviation of all targeted signs and symptoms of Covid-19 was 12 days in the nirmatrelvir-ritonavir group and 13 days in the placebo group (P = 0.60). Five participants (0.8%) in the nirmatrelvir-ritonavir group and 10 (1.6%) in the placebo group were hospitalized for Covid-19 or died from any cause (difference, -0.8 percentage points; 95% confidence interval, -2.0 to 0.4). The percentages of participants with adverse events were similar in the two groups (25.8% with nirmatrelvir-ritonavir and 24.1% with placebo). In the nirmatrelvir-ritonavir group, the most commonly reported treatment-related adverse events were dysgeusia (in 5.8% of the participants) and diarrhea (in 2.1%). CONCLUSIONS: The time to sustained alleviation of all signs and symptoms of Covid-19 did not differ significantly between participants who received nirmatrelvir-ritonavir and those who received placebo. (Supported by Pfizer; EPIC-SR ClinicalTrials.gov number, NCT05011513.).

Unrecognized volatile and semi-volatile organic compounds from brake wear.

Motor vehicles are among the major sources of pollutants and greenhouse gases in urban areas and a transition to "zero emission vehicles" is underway worldwide. However, emissions associated with brake and tire wear will remain. We show here that previously unrecognized volatile and semi-volatile organic compounds, which have a similarity to biomass burning emissions are emitted during braking. These include greenhouse gases or, these classified as Hazardous Air Pollutants, as well as nitrogen-containing organics, nitrogen oxides and ammonia. The distribution and reactivity of these gaseous emissions are such that they can react in air to form ozone and other secondary pollutants with adverse health and climate consequences. Some of the compounds may prove to be unique markers of brake emissions. At higher temperatures, nucleation and growth of nanoparticles is also observed. Regions with high traffic, which are often disadvantaged communities, as well as commuters can be impacted by these emissions even after combustion-powered vehicles are phased out.

Serum Troponin I Assessments in 5- to 30-Year-Olds After BNT162b2 Vaccination.

INTRODUCTION: Rare myocarditis and pericarditis cases have occurred in coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccine recipients. Troponin levels, a potential marker of myocardial injury, were assessed in healthy participants before and after BNT162b2 vaccination. METHODS: Vaccine-experienced 12- to 30-year-olds in phase 3 crossover C4591031 Substudy B (NCT04955626) who had two or three prior BNT162b2 30-µg doses were randomized to receive BNT162b2 30 µg followed by placebo, or placebo followed by BNT162b2 30 µg, 1 month apart. A participant subset, previously unvaccinated against COVID-19, in the phase 3 C4591007 study (NCT04816643) received up to three vaccinations (BNT162b2 10 µg or placebo [5- to 11-year-olds]) or open-label BNT162b2 30 µg (12- to 15-year-olds). Blood samples collected pre-vaccination, 4 days post-vaccination, and 1-month post-vaccination (C4591031 Substudy B only) were analyzed. Frequencies of elevated troponin I levels (male, > 35 ng/l; female, > 17 ng/l) were assessed. RESULTS: Percentages of 12- to 30-year-olds (n = 1485) in C4591031 Substudy B with elevated troponin levels following BNT162b2 or placebo receipt were 0.5% and 0.8% before vaccination, 0.7% and 1.0% at day 4, and 0.7% and 0.5% at 1 month, respectively. In Study C4591007 (n = 1265), elevated troponin I levels were observed in 0.2, 0.4, and 0.2% of 5- to 11-year-old BNT162b2 recipients at baseline and 4 days post-dose 2 and 3, respectively; corresponding values in 12- to 15-year-olds were 0.4, 0.4, and 0.7%. No 5- to 11-year-old placebo recipients had elevated troponin levels. No myocarditis or pericarditis cases or deaths were reported. CONCLUSIONS: Among 5- to < 30-year-olds in both studies, troponin levels were rarely elevated (≤ 1.0%) and similar before and post-vaccination; troponin levels were also similar between BNT162b2 and placebo in 12- to 30-year-old and 5- to 11-year-old recipients in the respective studies. No myocarditis or pericarditis cases were reported. These findings did not provide evidence that BNT162b2 causes troponin elevations. No utility of routine measurement of troponin levels in asymptomatic BNT162b2 recipients was identified.

[Translated article] Vancomycin powder in the prevention of infection in primary knee and hip arthroplasty: Case-control study with 1151 arthroplasties.

BACKGROUND AND OBJECTIVE: Vancomycin powder (VP) has been positively used in spinal surgery to reduce the rate of infections. Hardly any data have been published on hip and knee joint replacement surgery, and its usefulness is questioned. Our objective was to investigate the effectiveness of VP in reducing prosthetic infection and its possible complications. METHODS: Primary hip (THA) and knee (TKA) arthroplasties were reviewed, performed by five surgeons in one hospital centre, between 2017 and 2018. One gram of VP was used on the implant prior to surgical closure based on the surgeon's preferences. With a 5-year follow-up in which the infection rate and local complications were analysed. RESULTS: One thousand one hundred and fifty-one arthroplasties were performed, 748 were TKA and 403 were THA. Nine patients were diagnosed with prosthetic infection, of which five received VP and four did not (p=0.555). Likewise, another 15 patients suffered wound complications, of which 11 received VP and 4 did not (p=0.412). There were no differences, either, in the rest of the complications depending on the use or not of VP (p=0.101). Likewise, the number of patients who needed reintervention was similar (p=0.999). No systemic complications were detected due to the use of VP. CONCLUSIONS: It has not been possible to demonstrate that the use of VP reduces the rates of prosthetic infection in the hip and knee, so we cannot recommend its use.

Geographical differences in chronic obstructive pulmonary disease mortality trends by sex, Spain, 1980-2021.

BACKGROUND: To analyse changes in trends in mortality due to chronic obstructive pulmonary disease (COPD) in Spain by Autonomous Community (AC) and sex during the period 1980-2021.METHODS: Data on population and COPD death records (International Classification of Diseases, 10th edition, codes J40â-"J44 and J47) were retrieved from the National Institute of Statistics for the study period. Age-standardised mortality rates by AC and sex were assessed using joinpoint regression models.RESULTS: There were 562,668 deaths due to COPD (423,855 in men and 138,813 in women), with an average annual increase of 1.6%. COPD deaths in men increased in most ACs, except for Asturias (â-"0.5% per year). The Canary Islands (14% per year) and Madrid (6.5% per year) had the highest increases. In women, the figures show a wide range of values at the AC level (from a â-"1.4% decrease to 7.9% increase). Nationally, the sex ratio increased from 1980 to 2021. In men, six ACs showed a significant decrease, while in women only two ACs showed a significant decrease.CONCLUSION: A steady decrease in COPD mortality was observed in most ACs for men, while a different trend was observed in women in several ACs. Despite past and ongoing tobacco control initiatives, this condition remains a leading cause of death.

Vancomycin powder in the prevention of infection in primary knee and hip arthroplasty: Case-control study with 1151 arthroplasties. / Vancomicina en polvo en la prevención de la infección en artroplastia primaria de rodilla y cadera: estudio de casos y controles con 1.151 artroplastias.

BACKGROUND AND OBJECTIVE: Vancomycin powder (VP) has been positively used in spinal surgery to reduce the rate of infections. Hardly any data have been published on hip and knee joint replacement surgery, and its usefulness is questioned. Our objective was to investigate the effectiveness of VP in reducing prosthetic infection and its possible complications. METHODS: Primary hip (THA) and knee (TKA) arthroplasties were reviewed, performed by five surgeons in one hospital center, between 2017 and 2018. 1g of VP was used on the implant prior to surgical closure based on the surgeon's preferences. With a 5-year follow-up in which the infection rate and local complications were analyzed. RESULTS: One thousand one hundred and fifty one arthroplasties were performed, 748 were TKA and 403 were THA. Nine patients were diagnosed with prosthetic infection, of which five received VP and four did not (P=.555). Likewise, another 15 patients suffered wound complications, of which 11 received VP and 4 did not (P=.412). There were no differences, either, in the rest of the complications depending on the use or not of VP (P=.101). Likewise, the number of patients who needed reintervention was similar (P=.999). No systemic complications were detected due to the use of VP. CONCLUSIONS: It has not been possible to demonstrate that the use of VP reduces the rates of prosthetic infection in the hip and knee, so we cannot recommend its use.

Optical constraints on two-photon voltage imaging.

Genetically encoded voltage indicators (GEVIs) are a valuable tool for studying neural circuits in vivo, but the relative merits of one-photon (1P) vs. two-photon (2P) voltage imaging are not well characterized. Here we compare the photophysical and imaging properties of commonly used GEVIs under 1P and 2P excitation. 2P excitation requires ~104-fold more illumination power per cell to produce comparable photon count rates to 1P excitation, driving a stringent tradeoff between shot noise and tissue photodamage.

The Influence of Extracurricular Activities on Radiology Resident Selection Decisions.

PURPOSE: Extracurricular activities (EAs) listed on radiology residency applications can signal traits and characteristics desired in holistic reviews. The authors conducted an objective analysis to determine the influence of EAs on resident selection decisions. METHODS: A discrete-choice experiment was designed to model radiology resident selection and determine the relative weights of EAs among academic and demographic application factors. Faculty members involved in resident selection at 30 US radiology programs chose between hypothetical pairs of applicant profiles between October 2021 and February 2022. Each applicant profile included one of 22 EAs chosen for study. A conditional logistic regression model assessed the relative weights of the attributes and odds ratios (ORs) were calculated. RESULTS: Two hundred forty-four participants completed the exercise. Community-service EAs were ranked most highly by participants. LGBTQ Pride Alliance (OR, 1.56; 95% confidence interval [CI], 1.14-2.15; P = .006) and Young Republicans (OR, 0.60; 95% CI, 0.43-0.82; P = .001) significantly influenced decisions. The highest ranked EAs were significantly preferred over the lowest ranked EAs (OR, 1.916; 95% CI, 1.671-2.197; P < .001). Participants preferred EAs that reflected active over passive engagement (OR, 1.154; 95% CI, 1.022-1.304; P = .021) and progressive over conservative ideology (OR, 1.280; 95% CI, 1.133-1.447; P < .001). Participants who ranked progressive EAs more highly preferred applicants with progressive EAs (P < .05 for all). CONCLUSIONS: The influence of EAs on resident selection decisions is significant and likely to gain importance in resident selection as medical student performance metrics are further eliminated. Applicants and selection committees should consider this influence and the bias that EAs can bring to resident selection decisions.

A semi-automated microscopic image analysis method for scoring Ki-67 nuclear immunostaining.

Nuclear proliferation marker MIB-1 (Ki-67) immunohistochemistry (IHC) is used to examine tumor cell proliferation. However, the diagnostic or prognostic value of the Ki-67 nuclear staining intensity and location, defined as nuclear gradient (NG), has not been assessed. This study examined the potential association between Ki-67 NG and cell cycle phases and its effect on the prognosis of pulmonary typical carcinoid (PTC) tumors. We propose a method for classifying the NG of Ki-67 during the cell cycle and compare the results between PTC, pulmonary adenocarcinoma (PAD), and breast ductal carcinoma (BDC). A literature review and objective analysis of IHC-stained paraffin sections were used to determine the Ki-67 labeling index and composed a stratification of the NG into NG1, NG2, and NG3/4 categories. A semi-automated image analysis protocol was established to determine the Ki-67 NG in PTC, PAD, and BDC. High intraobserver consistency and moderate interobserver agreement were achieved in the determination of Ki-67 NG in tumor specimens. NG1 and NG2 were lower in PTC than in PAD and BDC. Cox multivariate analysis of PTC after adjusting for age and number of metastatic lymph nodes showed that Ki-67 NG1 and NG2 significantly predicted clinical outcomes. The semi-automated method for quantification of Ki-67 nuclear immunostaining proposed in this study could become a valuable diagnostic and prognostic tool in PTC.

A bioelectrical phase transition patterns the first vertebrate heartbeats.

A regular heartbeat is essential to vertebrate life. In the mature heart, this function is driven by an anatomically localized pacemaker. By contrast, pacemaking capability is broadly distributed in the early embryonic heart1-3, raising the question of how tissue-scale activity is first established and then maintained during embryonic development. The initial transition of the heart from silent to beating has never been characterized at the timescale of individual electrical events, and the structure in space and time of the early heartbeats remains poorly understood. Using all-optical electrophysiology, we captured the very first heartbeat of a zebrafish and analysed the development of cardiac excitability and conduction around this singular event. The first few beats appeared suddenly, had irregular interbeat intervals, propagated coherently across the primordial heart and emanated from loci that varied between animals and over time. The bioelectrical dynamics were well described by a noisy saddle-node on invariant circle bifurcation with action potential upstroke driven by CaV1.2. Our work shows how gradual and largely asynchronous development of single-cell bioelectrical properties produces a stereotyped and robust tissue-scale transition from quiescence to coordinated beating.

Variation in partial direct costs of treating clinical mastitis among 37 Wisconsin dairy farms.

The objective of this observational study was to describe variations in partial direct costs of clinical mastitis (CM) treatments among 37 dairy herds using data obtained from herd management records. Animal health and drug purchase records were retrospectively collected from 37 Wisconsin dairy herds for a period of 1 yr. Each farm was visited to verify case definitions, recording accuracy, and detection criteria of CM cases. Descriptive statistics were used to summarize cost of drugs and milk discard. Differences in costs among protocols, intramammary (IMM) products, parities, days in milk, and recurrence were analyzed using ANOVA. Of 20,625 cases of CM, 31% did not receive antimicrobial treatment. The average cost of drugs and milk discard (including cases that were not treated) was $192.36 ± 8.90 (mean ± SE) per case and ranged among farms from $118.13 to $337.25. For CM cases treated only with IMM antimicrobials, milk discard accounted for 87% of total costs and was highly influenced by duration of therapy. Differences in costs were observed among parities, recurrence, and stage of lactation at case detection. Eight different treatment protocols were observed, but 64% of cases were treated using only IMM antimicrobials. Treatment costs varied among protocols; however, cases treated using both IMM and injectable antimicrobials as well as supportive therapy had the greatest costs as they were also treated for the longest duration. Ceftiofur was used for 82% of cases that received IMM antimicrobials while ampicillin was used for 51% of cases treated using injectable antimicrobials. With the exception of ceftiofur and pirlimycin IMM products, many IMM products were given for durations that exceeded the maximum labeled duration. For cases treated using only IMM therapy, as compared with observed costs, we estimated that partial direct costs could be reduced by $65.20 per case if the minimum labeled durations were used. Overall, partial direct costs per case varied among herds, cow factors, and treatment protocols and were highly influenced by the duration of therapy.

Association of Neighborhood Deprivation With Healthcare Utilization Among Persons With Human Immunodeficiency Virus: A Latent Class Analysis.

Background: We previously identified 3 latent classes of healthcare utilization among people with human immunodeficiency virus (PWH): adherent, nonadherent, and sick. Although membership in the "nonadherent" group was associated with subsequent disengagement from human immunodeficiency virus (HIV) care, socioeconomic predictors of class membership remain unexplored. Methods: We validated our healthcare utilization-based latent class model of PWH receiving care at Duke University (Durham, North Carolina) using patient-level data from 2015 to 2018. SDI scores were assigned to cohort members based on residential addresses. Associations of patient-level covariates with class membership were estimated using multivariable logistic regression and movement between classes was estimated using latent transition analysis. Results: A total of 1443 unique patients (median age of 50 years, 28% female sex at birth, 57% Black) were included in the analysis. PWH in the most disadvantaged (highest) SDI decile were more likely to be in the "nonadherent" class than the remainder of the cohort (odds ratio [OR], 1.58 [95% confidence interval {CI}, .95-2.63]) and were significantly more likely to be in the "sick" class (OR, 2.65 [95% CI, 2.13-3.30]). PWH in the highest SDI decile were also more likely to transition into and less likely to transition out of the "sick" class. Conclusions: PWH who resided in neighborhoods with high levels of social deprivation were more likely to have latent class membership in suboptimal healthcare utilization groupings, and membership persisted over time. Risk stratification models based on healthcare utilization may be useful tools in the early identification of persons at risk for suboptimal HIV care engagement.

Mapping memories: pulse-chase labeling reveals AMPA receptor dynamics during memory formation.

A tool to map changes in synaptic strength during a defined time window could provide powerful insights into the mechanisms governing learning and memory. We developed a technique, Extracellular Protein Surface Labeling in Neurons (EPSILON), to map α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) insertion in vivo by pulse-chase labeling of surface AMPARs with membrane-impermeable dyes. This approach allows for single-synapse resolution maps of plasticity in genetically targeted neurons during memory formation. We investigated the relationship between synapse-level and cell-level memory encodings by mapping synaptic plasticity and cFos expression in hippocampal CA1 pyramidal cells upon contextual fear conditioning (CFC). We observed a strong correlation between synaptic plasticity and cFos expression, suggesting a synaptic mechanism for the association of cFos expression with memory engrams. The EPSILON technique is a useful tool for mapping synaptic plasticity and may be extended to investigate trafficking of other transmembrane proteins.

Voltage dynamics of dendritic integration and back-propagation in vivo.

Neurons integrate synaptic inputs within their dendrites and produce spiking outputs, which then propagate down the axon and back into the dendrites where they contribute to plasticity. Mapping the voltage dynamics in dendritic arbors of live animals is crucial for understanding neuronal computation and plasticity rules. Here we combine patterned channelrhodopsin activation with dual-plane structured illumination voltage imaging, for simultaneous perturbation and monitoring of dendritic and somatic voltage in Layer 2/3 pyramidal neurons in anesthetized and awake mice. We examined the integration of synaptic inputs and compared the dynamics of optogenetically evoked, spontaneous, and sensory-evoked back-propagating action potentials (bAPs). Our measurements revealed a broadly shared membrane voltage throughout the dendritic arbor, and few signatures of electrical compartmentalization among synaptic inputs. However, we observed spike rate acceleration-dependent propagation of bAPs into distal dendrites. We propose that this dendritic filtering of bAPs may play a critical role in activity-dependent plasticity.

Intercomparison of bidirectional reflectance distribution function measurements at in- and out-of-plane geometries.

In recent years, there has been a growing interest in the measurements of the bidirectional reflectance distribution function (BRDF) in industry and research and development. However, there is currently no dedicated key comparison to demonstrate the scale conformity. To date, scale conformity has been proved only for classical in-plane geometries, in comparisons between different national metrology institutes (NMIs) and designated institutes (DIs). This study aims at expanding that with nonclassical geometries, including, for the first time, to the best of our knowledge, two out-of-plane geometries. A total of four NMIs and two DIs participated in a scale comparison of the BRDF measurements of three achromatic samples at 550 nm in five measurement geometries. The realization of the scale of BRDF is a well-understood procedure, as explained in this paper, but the comparison of the measured values presents slight inconsistencies in some geometries, most likely due to the underestimation of measurement uncertainties. This underestimation was revealed and indirectly quantified using the Mandel-Paule method, which provides the interlaboratory uncertainty. The results from the presented comparison allow the present state of the BRDF scale realization to be evaluated, not only for classical in-plane geometries, but also for out-of-plane geometries.

Use of Patient Preferences Data Regarding Multiple Risks to Inform Regulatory Decisions.

Background and Objectives. Risk-tolerance measures from patient-preference studies typically focus on individual adverse events. We recently introduced an approach that extends maximum acceptable risk (MAR) calculations to simultaneous maximum acceptable risk thresholds (SMART) for multiple treatment-related risks. We extend these methods to include the computation and display of confidence intervals and apply the approach to 3 published discrete-choice experiments to evaluate its utility to inform regulatory decisions. Methods. We generate MAR estimates and SMART curves and compare them with trial-based benefit-risk profiles of select treatments for depression, psoriasis, and thyroid cancer. Results. In the depression study, SMART curves with 70% to 95% confidence intervals portray which combinations of 2 adverse events would be considered acceptable. In the psoriasis example, the asymmetric confidence intervals for the SMART curve indicate that relying on independent MARs versus SMART curves when there are nonlinear preferences can lead to decisions that could expose patients to greater risks than they would accept. The thyroid cancer application shows an example in which the clinical incidence of each of 3 adverse events is lower than the single-event MARs for the expected treatment benefit, yet the collective risk profile surpasses acceptable levels when considered jointly. Limitations. Nonrandom sample of studies. Conclusions. When evaluating conventional MARs in which the observed incidences are near the estimated MARs or where preferences demonstrate diminishing marginal disutility of risk, conventional MAR estimates will overstate risk acceptance, which could lead to misinformed decisions, potentially placing patients at greater risk of adverse events than they would accept. Implications. The SMART method, herein extended to include confidence intervals, provides a reproducible, transparent evidence-based approach to enable decision makers to use data from discrete-choice experiments to account for multiple adverse events. Highlights: Estimates of maximum acceptable risk (MAR) for a defined treatment benefit can be useful to inform regulatory decisions; however, the conventional metric considers one adverse event at a time.This article applies a new approach known as SMART (simultaneous maximum acceptable risk thresholds) that accounts for multiple adverse events to 3 published discrete-choice experiments.Findings reveal that conventional MARs could lead decision makers to accept a treatment based on individual risks that would not be acceptable if multiple risks are considered simultaneously.

Video-based pooled screening yields improved far-red genetically encoded voltage indicators.

Video-based screening of pooled libraries is a powerful approach for directed evolution of biosensors because it enables selection along multiple dimensions simultaneously from large libraries. Here we develop a screening platform, Photopick, which achieves precise phenotype-activated photoselection over a large field of view (2.3 × 2.3 mm, containing >103 cells, per shot). We used the Photopick platform to evolve archaerhodopsin-derived genetically encoded voltage indicators (GEVIs) with improved signal-to-noise ratio (QuasAr6a) and kinetics (QuasAr6b). These GEVIs gave improved signals in cultured neurons and in live mouse brains. By combining targeted in vivo optogenetic stimulation with high-precision voltage imaging, we characterized inhibitory synaptic coupling between individual cortical NDNF (neuron-derived neurotrophic factor) interneurons, and excitatory electrical synapses between individual hippocampal parvalbumin neurons. The QuasAr6 GEVIs are powerful tools for all-optical electrophysiology and the Photopick approach could be adapted to evolve a broad range of biosensors.