A taxonomy of demand-driven questions for use by evidence producers, intermediaries and decision-makers: results from a cross-sectional survey.

BACKGROUND: Globally, a growing number of calls to formalize and strengthen evidence-support systems have been released, all of which emphasize the importance of evidence-informed decision making. To achieve this, it is critical that evidence producers and decision-makers interact, and that decision-makers' evidence needs can be efficiently translated into questions to which evidence producers can respond. This paper aims to create a taxonomy of demand-driven questions for use by evidence producers, intermediaries (i.e., people working in between researchers and decision-makers) and decision-makers. METHODS: We conducted a global cross-sectional survey of units providing some type of evidence support at the explicit request of decision-makers. Unit representatives were invited to answer an online questionnaire where they were asked to provide a list of the questions that they have addressed through their evidence-support mechanism. Descriptive analyses were used to analyze the survey responses, while the questions collected from each unit were iteratively analyzed to create a mutually exclusive and collectively exhaustive list of types of questions that can be answered with some form of evidence. RESULTS: Twenty-nine individuals completed the questionnaire, and more than 250 submitted questions were analysed to create a taxonomy of 41 different types of demand-driven questions. These 41 questions were organized by the goal to be achieved, and the goals were grouped in the four decision-making stages (i) clarifying a societal problem, its causes and potential impacts; (ii) finding and selecting options to address a problem; (iii) implementing or scaling-up an option; and (iv) monitoring implementation and evaluating impacts. CONCLUSION: The mutually exclusive and collectively exhaustive list of demand-driven questions will help decision-makers (to ask and prioritize questions), evidence producers (to organize and present their work), and evidence-intermediaries (to connect evidence needs with evidence supply).

Quiescent frame, contrast-enhanced coronary magnetic resonance angiography reconstructed using limited number of physiologic frames from 5D free-running acquisitions.

BACKGROUND: 5D, free-running imaging resolves sets of 3D whole-heart images in both cardiac and respiratory dimensions. In an application such as coronary imaging when a single, static image is of interest, computationally expensive offline iterative reconstruction is still needed to compute the multiple 3D datasets. PURPOSE: Evaluate how the number of physiologic bins included in the reconstruction affects the computational cost and resulting image quality of a single, static volume reconstruction. STUDY TYPE: Retrospective. SUBJECTS: 15 pediatric patients following Ferumoxytol infusion (4 mg/kg). FIELD STRENGTH/SEQUENCE: 1.5 T/Ungated 5D free-running GRE sequence. ASSESSMENT: The raw data of each subject were binned and reconstructed into a 5D (x-y-z-cardiac-respiratory) images. 1, 3, 5, 7, and 9 bins adjacent to both sides of the retrospectively determined cardiac resting phase and 1, 3 bins adjacent to the end-expiration phase are used for limited frame reconstructions. The static volume within each limited reconstruction was compared with the corresponding full 5D reconstruction using the structural similarity index measure (SSIM). A non-linear regression model was used to fit SSIM with the percentage of data used compared to full reconstruction (% data). A linear regression model was used to fit computation time with % raw data used. Coronary artery sharpness is measured on each limited reconstructed images to determine the minimal number of cardiac and respiratory bins needed to preserve image quality. STATISTICAL TESTS: The coefficient of determination (R2) is computed for each regression model. RESULTS: The % of data used in the reconstruction was linearly related to the computational time (R2 = 0.99). The SSIM of the static image from the limited reconstructions is non-linearly related with the % of data used (R2 = 0.85). Over the 15 patients, the model showed SSIM of 0.9 with 22% of data, and SSIM of 0.95 with 45% of data. The coronary artery sharpness of images reconstructed using no less than 5 cardiac and all respiratory phases is not significantly different from the full reconstructed images using all cardiac and respiratory bins. DATA CONCLUSION: Reconstruction using only a limited number of acquired physiological states can linearly reduce the computational cost while preserving similarity to the full reconstruction image. It is suggested to use no less than 5 cardiac and all respiratory phases in the limited reconstruction to best preserve the original quality seen on the full reconstructed images.

Palladium-Catalyzed Amination of Aryl Halides with Aqueous Ammonia and Hydroxide Base Enabled by Ligand Development.

The conversion of aryl halides to primary arylamines with a convenient and inexpensive source of ammonia has been a long-standing synthetic challenge. Aqueous ammonia would be the most convenient and least expensive form of ammonia, but such a palladium-catalyzed amination reaction with a high concentration of water faces challenges concerning catalyst stability and competing hydroxylation, and palladium-catalyzed reactions with this practical reagent are rare. Further, most reactions with ammonia to form primary amines are conducted with tert-butoxide base, but reactions with ammonium hydroxide would contain hydroxide as base. Thus, ammonia surrogates, ammonia in organic solvents, and ammonium salts have been used under anhydrous conditions instead with varying levels of selectivity for the primary amine. We report the palladium-catalyzed amination of aryl and heteroaryl chlorides and bromides with aqueous ammonia and a hydroxide base to form the primary arylamine with high selectivity. The palladium catalyst containing a new dialkyl biheteroaryl phosphine ligand (KPhos) suppresses both the formation of aryl alcohol and diarylamine side products. Mechanistic studies with a soluble hydroxide base revealed turnover-limiting reductive elimination of the arylamine and an equilibrium between arylpalladium amido and hydroxo complexes prior to the turnover-limiting step.

Direct Lithium Extraction from α-Spodumene through Solid-State Reactions for Sustainable Li2CO3 Production.

With increasing battery demand comes a need for diversified Li sources beyond brines. Among all Li-bearing minerals, spodumene is most often used for its high Li content and natural abundance. However, the traditional approach to process spodumene is costly and energy-intensive, requiring the mineral be transformed from its natural α to ß phase at >1000 °C. Acid leaching is then applied, followed by neutralization to precipitate Li2CO3. In this work, we report an alternative method to extract Li directly from α-spodumene, which is performed at lower temperatures and avoids the use of acids. It is shown that Li2CO3 is formed with >90% yield at 750 °C by reacting α-spodumene with Na2CO3 and Al2O3. The addition of Al2O3 is critical to reduce the amount of Li2SiO3 that forms when only Na2CO3 is used, instead providing increased thermodynamic driving force to form NaAlSiO4 and Li2CO3 as the sole products. We find that this reaction is most effective at 4 h, after which volatility limits the yield. Following its extraction, Li2CO3 can be isolated by washing the sample using deionized water. This energy-saving and acid-free route to obtain Li2CO3 directly from spodumene can help meet the growing demand for Li.

Education for Integration: Dental hygiene student and family medicine residents.

Purpose The integration of oral health and primary care offers promising solutions to overcome barriers hindering patient access to oral health care. However, primary care providers require training in basic preventive oral health care and information regarding interprofessional practice opportunities. The purpose of this feasibility study was to examine the perspective of families, learners, faculty, and administrators who engaged in an interprofessional training experience for family medicine residents and dental hygiene students.Methods Family medicine residents and dental hygiene students participated in an interprofessional oral health integration training experience, which included didactic, preclinical, and clinical components. The clinical experience was conducted during a Medicaid Managed Care clinic session, which included the participation of children who had not undergone a well-child visit within the past year. The care teams were comprised of a family medicine resident and dental hygiene student, who collaborated on the provision of preventive oral health care services, including oral examinations, preventive interventions, patient education, and care coordination. Qualitative data gathered using field notes, focus groups, and key informant interviews were analyzed to identify themes from care team, patient/family, and administrative perspectives.Results The care teams provided preventive health oral health care services to 10 pediatric patients during their well child visit. Patients and family members reported appreciating the convenience and value of the care provided. The experience was well received by family medicine residents, dental hygiene students, and clinical faculty members, who highlighted the value of the experience in expanding access to care. The family medicine residents reported the training and interprofessional practice opportunity to be highly valuable, reporting better preparation for the identification, evaluation, and treatment of oral conditions that they may have otherwise overlooked or misdiagnosed.Conclusions This interprofessional educational experience demonstrates the potential value of integrating preventive oral health in primary care visits for children. This care integration may be especially helpful for populations that experience barriers to oral health care. Results of this study suggest that expanding interprofessional education between dental hygiene programs and family medicine residencies may be beneficial for preparing the future workforce for integrated care. Additional research is needed to formalize training models that support integration and promote interprofessional collaboration and practice.

Neuronal activity-driven O-GlcNAcylation promotes mitochondrial plasticity.

Neuronal activity is an energy-intensive process that is largely sustained by instantaneous fuel utilization and ATP synthesis. However, how neurons couple ATP synthesis rate to fuel availability is largely unknown. Here, we demonstrate that the metabolic sensor enzyme O-linked N-acetyl glucosamine (O-GlcNAc) transferase regulates neuronal activity-driven mitochondrial bioenergetics in hippocampal and cortical neurons. We show that neuronal activity upregulates O-GlcNAcylation in mitochondria. Mitochondrial O-GlcNAcylation is promoted by activity-driven glucose consumption, which allows neurons to compensate for high energy expenditure based on fuel availability. To determine the proteins that are responsible for these adjustments, we mapped the mitochondrial O-GlcNAcome of neurons. Finally, we determine that neurons fail to meet activity-driven metabolic demand when O-GlcNAcylation dynamics are prevented. Our findings suggest that O-GlcNAcylation provides a fuel-dependent feedforward control mechanism in neurons to optimize mitochondrial performance based on neuronal activity. This mechanism thereby couples neuronal metabolism to mitochondrial bioenergetics and plays a key role in sustaining energy homeostasis.

Multi-sequence MRI-based radiomics: An objective method to diagnose early-stage osteonecrosis of the femoral head.

OBJECTIVES: This study investigated the use of radiomics for diagnosing early-stage osteonecrosis of the femoral head (ONFH) by extracting features from multiple MRI sequences and constructing predictive models. MATERIALS AND METHODS: We conducted a retrospective review, collected MR images of early-stage ONFH (102 from institution A and 20 from institution B) and healthy femoral heads (102 from institution A and 20 from institution B) from two institutions. We extracted radiomics features, handled batch effects using Combat, and normalized features using z-score. We employed the Least absolute shrinkage and selection operator (LASSO) algorithm, along with Max-Relevance and Min-Redundancy (mRMR), to select optimal features for constructing radiomics models based on single, double, and multi-sequence MRI data. We evaluated performance using receiver operating characteristic (ROC) and precision-recall (PR) curves, and compared area under curve of ROC (AUC-ROC) values with the DeLong test. Additionally, we studied the diagnostic performance of the multi-sequence radiomics model and radiologists, compared the diagnostic outcomes of the model and radiologists using the Fisher exact test. RESULTS: We studied 122 early-stage ONFH and 122 normal femoral heads. The multi-sequence model exhibited the best diagnostic performance among all models (AUC-ROC, PR-AUC for training set: 0.96, 0.961; validation set: 0.96, 0.97; test set: 0.94, 0.94), and it outperformed three resident radiologists on the external testing group with an accuracy of 87.5 %, sensitivity of 85.00 %, and specificity of 90.00 % (p < 0.01), highlighting the robustness of our findings. CONCLUSIONS: Our study underscored the novelty of the multi-sequence radiomics model in diagnosing early-stage ONFH. By leveraging features extracted from multiple imaging sequences, this approach demonstrated high efficacy, indicating its potential to advance early diagnosis for ONFH. These findings provided important guidance for enhancing early diagnosis of ONFH through radiomics methods, offering new avenues and possibilities for clinical practice and patient care.

The cryoEM structure of the Hendra henipavirus nucleoprotein reveals insights into paramyxoviral nucleocapsid architectures.

We report the first cryoEM structure of the Hendra henipavirus nucleoprotein in complex with RNA, at 3.5 Å resolution, derived from single particle analysis of a double homotetradecameric RNA-bound N protein ring assembly exhibiting D14 symmetry. The structure of the HeV N protein adopts the common bi-lobed paramyxoviral N protein fold; the N-terminal and C-terminal globular domains are bisected by an RNA binding cleft containing six RNA nucleotides and are flanked by the N-terminal and C-terminal arms, respectively. In common with other paramyxoviral nucleocapsids, the lateral interface between adjacent Ni and Ni+1 protomers involves electrostatic and hydrophobic interactions mediated primarily through the N-terminal arm and globular domains with minor contribution from the C-terminal arm. However, the HeV N multimeric assembly uniquely identifies an additional protomer-protomer contact between the Ni+1 N-terminus and Ni-1 C-terminal arm linker. The model presented here broadens the understanding of RNA-bound paramyxoviral nucleocapsid architectures and provides a platform for further insight into the molecular biology of HeV, as well as the development of antiviral interventions.

Sex differences in coronary atherosclerotic plaque activity using 18F-sodium fluoride positron emission tomography.

INTRODUCTION: There are sex differences in the extent, severity, and outcomes of coronary artery disease. We aimed to assess the influence of sex on coronary atherosclerotic plaque activity measured using coronary 18F-sodium fluoride (18F-NaF) positron emission tomography (PET), and to determine whether 18F-NaF PET has prognostic value in both women and men. METHODS: In a post-hoc analysis of observational cohort studies of patients with coronary atherosclerosis who had undergone 18F-NaF PET CT angiography, we compared the coronary microcalcification activity (CMA) in women and men. RESULTS: Baseline 18F-NaF PET CT angiography was available in 999 participants (151 (15%) women) with 4282 patient-years of follow-up. Compared to men, women had lower coronary calcium scores (116 [interquartile range, 27-434] versus 205 [51-571] Agatston units; p = 0.002) and CMA values (0.0 [0.0-1.12] versus 0.53 [0.0-2.54], p = 0.01). Following matching for plaque burden by coronary calcium scores and clinical comorbidities, there was no sex-related difference in CMA values (0.0 [0.0-1.12] versus 0.0 [0.0-1.23], p = 0.21) and similar proportions of women and men had no 18F-NaF uptake (53.0% (n = 80) and 48.3% (n = 73); p = 0.42), or CMA values > 1.56 (21.8% (n = 33) and 21.8% (n = 33); p = 1.00). Over a median follow-up of 4.5 [4.0-6.0] years, myocardial infarction occurred in 6.6% of women (n = 10) and 7.8% of men (n = 66). Coronary microcalcification activity greater than 0 was associated with a similarly increased risk of myocardial infarction in both women (HR: 3.83; 95% CI:1.10-18.49; p = 0.04) and men (HR: 5.29; 95% CI:2.28-12.28; p < 0.001). CONCLUSION: Although men present with more coronary atherosclerotic plaque than women, increased plaque activity is a strong predictor of future myocardial infarction regardless of sex.

Improving the representativeness of UK's national COVID-19 Infection Survey through spatio-temporal regression and post-stratification.

Population-representative estimates of SARS-CoV-2 infection prevalence and antibody levels in specific geographic areas at different time points are needed to optimise policy responses. However, even population-wide surveys are potentially impacted by biases arising from differences in participation rates across key groups. Here, we used spatio-temporal regression and post-stratification models to UK's national COVID-19 Infection Survey (CIS) to obtain representative estimates of PCR positivity (6,496,052 tests) and antibody prevalence (1,941,333 tests) for different regions, ages and ethnicities (7-December-2020 to 4-May-2022). Not accounting for vaccination status through post-stratification led to small underestimation of PCR positivity, but more substantial overestimations of antibody levels in the population (up to 21 percentage points), particularly in groups with low vaccine uptake in the general population. There was marked variation in the relative contribution of different areas and age-groups to each wave. Future analyses of infectious disease surveys should take into account major drivers of outcomes of interest that may also influence participation, with vaccination being an important factor to consider.

THE ECONOMIC IMPACTS OF COVID-19: EVIDENCE FROM A NEW PUBLIC DATABASE BUILT USING PRIVATE SECTOR DATA.

We build a publicly available database that tracks economic activity in the United States at a granular level in real time using anonymized data from private companies. We report weekly statistics on consumer spending, business revenues, job postings, and employment rates disaggregated by county, sector, and income group. Using the publicly available data, we show how the COVID-19 pandemic affected the economy by analyzing heterogeneity in its effects across subgroups. High-income individuals reduced spending sharply in March 2020, particularly in sectors that require in-person interaction. This reduction in spending greatly reduced the revenues of small businesses in affluent, dense areas. Those businesses laid off many of their employees, leading to widespread job losses, especially among low-wage workers in such areas. High-wage workers experienced a V-shaped recession that lasted a few weeks, whereas low-wage workers experienced much larger, more persistent job losses. Even though consumer spending and job postings had recovered fully by December 2021, employment rates in low-wage jobs remained depressed in areas that were initially hard hit, indicating that the temporary fall in labor demand led to a persistent reduction in labor supply. Building on this diagnostic analysis, we evaluate the effects of fiscal stimulus policies designed to stem the downward spiral in economic activity. Cash stimulus payments led to sharp increases in spending early in the pandemic, but much smaller responses later in the pandemic, especially for high-income households. Real-time estimates of marginal propensities to consume provided better forecasts of the impacts of subsequent rounds of stimulus payments than historical estimates. Overall, our findings suggest that fiscal policies can stem secondary declines in consumer spending and job losses, but cannot restore full employment when the initial shock to consumer spending arises from health concerns. More broadly, our analysis demonstrates how public statistics constructed from private sector data can support many research and real-time policy analyses, providing a new tool for empirical macroeconomics.

Antibody levels following vaccination of beef calves with a tetanus toxoid.

Tetanus is a preventable, yet often fatal, disease affecting many species, including beef cattle. Vaccination for tetanus is recommended for calves at high risk of disease, but typical beef cattle management practices often make adherence to vaccine manufacturers' guidance for a second (booster) dose of vaccine difficult. This study examined the antibody response following a single dose of tetanus toxoid, as well as following booster vaccination at various intervals. Anti-tetanus IgG antibodies were detectable 25 days (D25) after a single dose, and rose following booster at either D25 D109 after initial vaccination. Antibody levels then declined numerically from D109 to D179 for calves boostered at D25 but rose on D179 for those receiving a second dose on D109. The relatively rapid response in IgG production, even in the absence of a booster vaccine, may suggest value in vaccinating calves for tetanus at time of greatest risk, even if a booster cannot be administered. The study also provides support for priming of the immune response lasting at least until D109 after primary immunization.

Tentonin 3 is a pore-forming subunit of a slow inactivation mechanosensitive channel.

Mechanically activating (MA) channels transduce numerous physiological functions. Tentonin 3/TMEM150C (TTN3) confers MA currents with slow inactivation kinetics in somato- and barosensory neurons. However, questions were raised about its role as a Piezo1 regulator and its potential as a channel pore. Here, we demonstrate that purified TTN3 proteins incorporated into the lipid bilayer displayed spontaneous and pressure-sensitive channel currents. These MA currents were conserved across vertebrates and differ from Piezo1 in activation threshold and pharmacological response. Deep neural network structure prediction programs coupled with mutagenetic analysis predicted a rectangular-shaped, tetrameric structure with six transmembrane helices and a pore at the inter-subunit center. The putative pore aligned with two helices of each subunit and had constriction sites whose mutations changed the MA currents. These findings suggest that TTN3 is a pore-forming subunit of a distinct slow inactivation MA channel, potentially possessing a tetrameric structure.

Cellular endosomal potassium ion flux regulates arenavirus uncoating during virus entry.

Lymphocytic choriomeningitis virus (LCMV) is an enveloped and segmented negative-sense RNA virus classified within the Arenaviridae family of the Bunyavirales order. LCMV is associated with fatal disease in immunocompromised populations and, as the prototypical arenavirus member, acts as a model for the many highly pathogenic members of the Arenaviridae family, such as Junín, Lassa, and Lujo viruses, all of which are associated with devastating hemorrhagic fevers. To enter cells, the LCMV envelope fuses with late endosomal membranes, for which two established requirements are low pH and interaction between the LCMV glycoprotein (GP) spike and secondary receptor CD164. LCMV subsequently uncoats, where the RNA genome-associated nucleoprotein (NP) separates from the Z protein matrix layer, releasing the viral genome into the cytosol. To further examine LCMV endosome escape, we performed an siRNA screen which identified host cell potassium ion (K+) channels as important for LCMV infection, with pharmacological inhibition confirming K+ channel involvement during the LCMV entry phase completely abrogating productive infection. To better understand the K+-mediated block in infection, we tracked incoming virions along their entry pathway under physiological conditions, where uncoating was signified by separation of NP and Z proteins. In contrast, K+ channel blockade prevented uncoating, trapping virions within Rab7 and CD164-positive endosomes, identifying K+ as a third LCMV entry requirement. K+ did not increase GP-CD164 binding or alter GP-CD164-dependent fusion. Thus, we propose that K+ mediates uncoating by modulating NP-Z interactions within the virion interior. These results suggest K+ channels represent a potential anti-arenaviral target.IMPORTANCEArenaviruses can cause fatal human disease for which approved preventative or therapeutic options are not available. Here, using the prototypical LCMV, we identified K+ channels as critical for arenavirus infection, playing a vital role during the entry phase of the infection cycle. We showed that blocking K+ channel function resulted in entrapment of LCMV particles within late endosomal compartments, thus preventing productive replication. Our data suggest K+ is required for LCMV uncoating and genome release by modulating interactions between the viral nucleoprotein and the matrix protein layer inside the virus particle.

Tenecteplase versus alteplase for thrombolysis in patients selected by use of perfusion imaging within 4·5 h of onset of ischaemic stroke (TASTE): a multicentre, randomised, controlled, phase 3 non-inferiority trial.

BACKGROUND: Intravenous tenecteplase increases reperfusion in patients with salvageable brain tissue on perfusion imaging and might have advantages over alteplase as a thrombolytic for ischaemic stroke. We aimed to assess the non-inferiority of tenecteplase versus alteplase on clinical outcomes in patients selected by use of perfusion imaging. METHODS: This international, multicentre, open-label, parallel-group, randomised, clinical non-inferiority trial enrolled patients from 35 hospitals in eight countries. Participants were aged 18 years or older, within 4·5 h of ischaemic stroke onset or last known well, were not being considered for endovascular thrombectomy, and met target mismatch criteria on brain perfusion imaging. Patients were randomly assigned (1:1) by use of a centralised web server with randomly permuted blocks to intravenous tenecteplase (0·25 mg/kg) or alteplase (0·90 mg/kg). The primary outcome was the proportion of patients without disability (modified Rankin Scale 0-1) at 3 months, assessed via masked review in both the intention-to-treat and per-protocol populations. We aimed to recruit 832 participants to yield 90% power (one-sided alpha=0·025) to detect a risk difference of 0·08, with an absolute non-inferiority margin of -0·03. The trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000243718, and the European Union Clinical Trials Register, EudraCT Number 2015-002657-36, and it is completed. FINDINGS: Recruitment ceased early following the announcement of other trial results showing non-inferiority of tenecteplase versus alteplase. Between March 21, 2014, and Oct 20, 2023, 680 patients were enrolled and randomly assigned to tenecteplase (n=339) and alteplase (n=341), all of whom were included in the intention-to-treat analysis (multiple imputation was used to account for missing primary outcome data for five patients). Protocol violations occurred in 74 participants, thus the per-protocol population comprised 601 people (295 in the tenecteplase group and 306 in the alteplase group). Participants had a median age of 74 years (IQR 63-82), baseline National Institutes of Health Stroke Scale score of 7 (4-11), and 260 (38%) were female. In the intention-to-treat analysis, the primary outcome occurred in 191 (57%) of 335 participants allocated to tenecteplase and 188 (55%) of 340 participants allocated to alteplase (standardised risk difference [SRD]=0·03 [95% CI -0·033 to 0·10], one-tailed pnon-inferiority=0·031). In the per-protocol analysis, the primary outcome occurred in 173 (59%) of 295 participants allocated to tenecteplase and 171 (56%) of 306 participants allocated to alteplase (SRD 0·05 [-0·02 to 0·12], one-tailed pnon-inferiority=0·01). Nine (3%) of 337 patients in the tenecteplase group and six (2%) of 340 in the alteplase group had symptomatic intracranial haemorrhage (unadjusted risk difference=0·01 [95% CI -0·01 to 0·03]) and 23 (7%) of 335 and 15 (4%) of 340 died within 90 days of starting treatment (SRD 0·02 [95% CI -0·02 to 0·05]). INTERPRETATION: The findings in our study provide further evidence to strengthen the assertion of the non-inferiority of tenecteplase to alteplase, specifically when perfusion imaging has been used to identify reperfusion-eligible stroke patients. Although non-inferiority was achieved in the per-protocol population, it was not reached in the intention-to-treat analysis, possibly due to sample size limtations. Nonetheless, large-scale implementation of perfusion CT to assist in patient selection for intravenous thrombolysis in the early time window was shown to be feasible. FUNDING: Australian National Health Medical Research Council; Boehringer Ingelheim.

Quantifying Sagittal Lip Changes in Patients with Bilateral Cleft Lip Post Abbe Flap Reconstruction.

OBJECTIVES: To objectively quantify results of sagittal lip changes following Abbe flap reconstruction in patients with bilateral cleft lip. DESIGN: Retrospective, observational study. SETTING: Single institution, 8-year retrospective review. PATIENTS/PARTICIPANTS: In total, 17 patients with bilateral cleft lip that underwent Abbe flap reconstruction were included in this study. INTERVENTION: Patients had lateral photographs taken prior to Abbe flap reconstruction and at least 8 months post-Abbe flap. MAIN OUTCOME MEASUREMENTS: Vegter's index, Sushner's S2 line and Burstone's B line reference lines were used for evaluation of sagittal lip changes. Wilcoxon signed rank tests were used in analysis. RESULTS: The mean pre-Abbe flap upper to lower lip ratio, defined as Vegter's Lip Index, was 0.906 compared to a mean of 0.946 following Abbe flap reconstruction. The mean upper to lower lip ratio for Sushner's S2 and Burstone's B line exhibited an increase in upper lip sagittal projection from -0.164 to 1.459 and 0.259 to 0.957, respectively (P < 0.001). CONCLUSIONS: This study quantifies sagittal changes to upper and lower lip position after Abbe flap reconstruction. These findings may aid in operative planning and patient/caregiver expectations during counseling.

The relationship between healthcare access and change in health-related quality-of-life among the general population of five countries during the COVID-19 pandemic.

PURPOSE: To determine whether (1) healthcare access at onset of the pandemic and (2) age, gender, socioeconomic status (SES), and pre-existing health status were associated with change in health-related quality-of-life (HRQoL) during the COVID-19 pandemic. The study includes a general population sample of five countries. METHODS: An online questionnaire was administered to respondents from Greece, Italy, the Netherlands, the UK, and the US at the onset of the COVID-19 pandemic between April 22nd and May 5th of 2020, and 1 year later between May 23rd and June 29th of 2021. The questionnaire included questions on demographic background, health status, and HRQoL. The primary outcome was change in HRQoL as measured by the EQ-5D-5L instrument. Specifically, the EQ-5D-5L index and EQ VAS were used. Healthcare access was quantified with regard to the respondent's ease of getting an appointment, waiting time, and opportunity to contact the provider and during analysis dichotomized into "sufficient" versus "insufficient". Linear regression analysis was performed with change in HRQoL as dependent variable and background variables as independent variables. RESULTS: In total, 6,765 respondents completed the second questionnaire. 19.8% of total respondents reported insufficient healthcare access. Respondents with insufficient healthcare had both more improved and deteriorated HRQoL compared to respondents with sufficient healthcare, whose HRQoL remained unchanged. We did not find significant interactions between age, gender, SES and/or chronic disease status with healthcare access at onset of the COVID-19 pandemic. CONCLUSION: Healthcare access was not associated with cumulative differences in change in HRQoL over a 1-year period in strata of age, gender, SES, and chronic disease status.

Molecular organization of autonomic, respiratory, and spinally-projecting neurons in the mouse ventrolateral medulla.

The ventrolateral medulla (VLM) is a crucial region in the brain for visceral and somatic control, serving as a significant source of synaptic input to the spinal cord. Experimental studies have shown that gene expression in individual VLM neurons is predictive of their function. However, the molecular and cellular organization of the VLM has remained uncertain. This study aimed to create a comprehensive dataset of VLM cells using single-cell RNA sequencing in male and female mice. The dataset was enriched with targeted sequencing of spinally-projecting and adrenergic/noradrenergic VLM neurons. Based on differentially expressed genes, the resulting dataset of 114,805 VLM cells identifies 23 subtypes of neurons, excluding those in the inferior olive, and 5 subtypes of astrocytes. Spinally-projecting neurons were found to be abundant in 7 subtypes of neurons, which were validated through in-situ hybridization. These subtypes included adrenergic/noradrenergic neurons, serotonergic neurons, and neurons expressing gene markers associated with pre-motor neurons in the ventromedial medulla. Further analysis of adrenergic/noradrenergic neurons and serotonergic neurons identified 9 and 6 subtypes, respectively, within each class of monoaminergic neurons. Marker genes that identify the neural network responsible for breathing were concentrated in 2 subtypes of neurons, delineated from each other by markers for excitatory and inhibitory neurons. These datasets are available for public download and for analysis with a user-friendly interface. Collectively, this study provides a fine-scale molecular identification of cells in the VLM, forming the foundation for a better understanding of the VLM's role in vital functions and motor control.Significance statement The ventrolateral medulla (VLM) is an anatomically complex region of the brain that plays a crucial role in regulating vital functions, including autonomic and respiratory control, sleep-wake behaviors, cranial motor functions, and locomotion. This study comprehensively classifies VLM cell types and neuronal subtypes based on their molecular and anatomical features, by leveraging single-nuclei RNA sequencing, RNA fluorescence in situ hybridization, and axonal tract tracing. We present a dataset comprising 114,805 single-nuclei transcriptomes that identifies and validates the precise molecular characteristics of neurons involved in autonomic and motor systems functions. This publicly-available dataset offers new opportunities for comprehensive experimental studies to dissect the central organization of vital homeostatic functions and body movement.