Notes

Overview of Actuation and Feeling Elements throughout MEMS-Based Sensing unit Units.
coli TRFC. The analysis of metabolic flux distribution indicated that the flux of threonine with E. coli TRFC-AP reached 69.8%, an increase of 16.0% compared with that of E. coli TRFC. Overall, higher L-threonine production and glucose conversion percentage were obtained with E. coli TRFC-AP due to increased activities of key enzymes and improved carbon flux for threonine synthesis.
Children with brain tumor or acute leukemia are at risk for neurotoxic side effects associated with their cancer therapies. These long-term deficits include poor health-related quality of life (HRQOL) in school and lower educational achievement. Although social-ecological factors may impact these outcomes, it is not known which factors play a role. Our objective was to evaluate the factors affecting school HRQOL in Hispanic childhood cancer survivors, an important at-risk group.

Multivariable regression analyses examined whether selected social-ecological factors contribute toward suboptimal school HRQOL in 73 Hispanic children treated with central nervous system (CNS)-directed cancer therapies after accounting for effects associated with established cancer-related risk factors.

Consistent with expectations from prior research, in our multivariate analysis, the cancer-related factors of having a brain tumor diagnosis and being younger at cancer diagnosis were significant predictors of reduced parent-rep. Future research should consider other at-risk groups and incorporate social-ecological indicators to predict HRQOL outcomes.
What is the central question of this study? What is the impact of airway cholinergic history on the properties of airway mucus secretion in a cystic fibrosis-like environment? What is the main finding and its importance? Prior cholinergic challenge slightly modifies the characteristics of mucus secretion in response to a second cholinergic challenge in a diminished bicarbonate and chloride transport environment. Such modifications might lead to retention of mucus on the airway surface, thereby potentiating exacerbations of airway disease.

Viral infections precipitate exacerbations in many airway diseases, including asthma and cystic fibrosis. Although viral infections increase cholinergic transmission, few studies have examined how cholinergic history modifies subsequent cholinergic responses in the airway. In our previous work, we found that airway resistance in response to a second cholinergic challenge was increased in young pigs with a history of airway cholinergic stimulation. Given that mucus secrettitive stimulation might lead to retention of mucus on the airway surface, thereby potentiating exacerbations of airway disease.High-throughput (HT) enzymatic assays, which typically rely on labeled compounds and plate readers, are important for drug discovery. Mass spectrometry (MS) provides an alternative method of performing HT label-free assays. Here we demonstrate the use of a HT platform based on desorption electrospray ionization (DESI) MS for the label-free study of enzymatic reactions directly from the bioassay matrix with an effective analysis time of 0.3 s per sample. This system allows for thorough analysis of the enzymatic process through monitoring of its substrate and product after an external calibration. We show the platform capabilities by an in-depth study of the acetylcholinesterase assay, including kinetic parameter determination, rapid inhibitor screening, and further characterization of positive hits (that is, IC50 and Ki ), as well as inhibition-reactivation assays. We anticipate that the expansion of this platform has high potential impact in label-free enzymology as well as in drug discovery.
Irritable bowel disease (IBD) is a gastrointestinal disorder characterized by chronic granulomatous inflammation of the entire digestive system, which includes the oral cavity. Oral manifestations of IBD includes aphthous ulcerations which may appear spontaneously and resemble episodes of active flare ups of IBD. The presence of oral mucosal ulcerations, in addition with other systemic symptoms and exclusion of other etiological causes, requires an interdisciplinary team approach to diagnose and manage.

A 19-year-old female presented with significant ulcerations next to a surgical site after a tooth extraction and ridge preservation procedure. The patient reported a history of preexisting episodes of ulcerations and continued to develop ulcers while the surgical site was healing. A referral to a gastroenterologist lead to a confirmed diagnosis of IBD.

This case report presents a case of mucosal ulceration after surgical intervention that lead to the diagnosis of IBD. Appropriate and timely identification of oral manifestations of systemic disease conditions is key in early diagnosis and disease management. Connecting oral lesions to early presentation of systemic conditions potentially reduces a patient's systemic disease burden and improves their quality of life.
This case report presents a case of mucosal ulceration after surgical intervention that lead to the diagnosis of IBD. Appropriate and timely identification of oral manifestations of systemic disease conditions is key in early diagnosis and disease management. Connecting oral lesions to early presentation of systemic conditions potentially reduces a patient's systemic disease burden and improves their quality of life.
Representation of benefits and harms associated with specific interventions in an understandable and comparable way is crucial for informed decision making that clinical practice guidelines (CPGs) aim to enhance. Therefore, we investigated how statements concerning the effects of interventions considered and described benefits and harms, magnitude of effect and its uncertainty, numeric and non-numeric information, and outcomes in Finnish CPGs.

We selected 10 CPGs on common diseases and risk factors published by The Finnish Medical Society, Duodecim. All the statements which were graded with the level of evidence from high to very low (levels A-D) were included in analyses. From these statements, assessments were made regarding whether the statement considered benefits or harms, whether relative or absolute numeric measures were shown, whether the statement supported or was against the intervention considered, and what outcome was reported.

Of the 10 CPGs, 448 statements were assessed. Most of the statemdered intervention benefits (87%) rather than harms. Half of the statements considering harms were represented in a way that supported the intervention. Most of the statements (94%) did not include numeric estimates of magnitude of the effect. When numeric estimates of magnitude of the effect were present, they were most frequently relative measures and were typically placed in a statement considering (a) intervention benefits with a primary outcome, (b) given the grade of A for level of evidence, and (c) that supported the use of intervention. Conclusions In the Finnish CPGs, the statements were rarely framed with both absolute and relative numeric measures of an intervention's effect. Harms were rarely reported with a grade indicating the level of evidence. The users of CPGs would benefit from more consistent and understandable framing of statements considering both benefits and harms of interventions.
Increasing appropriate HIV testing among men who have sex with men (MSM) is crucial to HIV prevention. Mass media interventions are effective in promoting testing, but to date, there has been little examination of their active content.

We conducted a qualitative analysis of intervention materials (n=69) derived from a systematic review of mass media interventions designed to improve testing with MSM.

Visual data were analysed for their affective and ideological content using a novel method drawing on concepts from semiotics (i.e., broadly speaking, the analysis of signs).

Whilst affect was not explicitly theorized or examined in any of the studies, there are clearly identifiable affective elements implicitly at play in these interventions. Four thematic categories of affect/ideology were identified including (1) sexual desire and the 'pornographication' of the gay/bisexual male subject; (2) narratives of romance and love; (3) fear, threat, and regret; and (4) 'flattened' affect.

This is the first study to examine and detail the affective and ideological aspects of intervention content in this field. Using analytic techniques such as those reported here, in addition to approaches that focus on the manner in which intervention content address more proximal determinants of behaviour, can provide a rich and potentially more useful evidence base to assist with future interventions.
This is the first study to examine and detail the affective and ideological aspects of intervention content in this field. Using analytic techniques such as those reported here, in addition to approaches that focus on the manner in which intervention content address more proximal determinants of behaviour, can provide a rich and potentially more useful evidence base to assist with future interventions.Synthetic chemicals are frequently detected in water bodies, and their concentrations vary over time. Water monitoring programs typically employ either a sequence of grab samples or continuous sampling, followed by chemical analysis. Continuous time-proportional sampling yields the time-weighted average concentration, which is taken as proxy for the real, time-variable exposure. However, we do not know how much the toxicity of the average concentration differs from the toxicity of the corresponding fluctuating exposure profile. We used toxicokinetic-toxicodynamic models (invertebrates, fish) and population growth models (algae, duckweed) to calculate the margin of safety in moving time windows across measured aquatic concentration time series (7 pesticides) in 5 streams. A longer sampling period (14 d) for time-proportional sampling leads to more deviations from the real chemical stress than shorter sampling durations (3 d). The associated error is a factor of 4 or less in the margin of safety value toward underestimating and an error of factor 9 toward overestimating chemical stress in the most toxic time windows. Under- and overestimations occur with approximate equal frequency and are very small compared with the overall variation, which ranged from 0.027 to 2.4 × 1010 (margin of safety values). We conclude that continuous, time-proportional sampling for a period of 3 and 14 d for acute and chronic assessment, respectively, yields sufficiently accurate average concentrations to assess ecotoxicological effects. Environ Toxicol Chem 2020;392158-2168. © 2020 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.
Ketone bodies are proposed to represent an alternative fuel source driving energy production, particularly during exercise. Biologically, the extent to which mitochondria utilize ketone bodies compared to other substrates remains unknown. We demonstrate in vitro that maximal mitochondrial respiration supported by ketone bodies is low when compared to carbohydrate-derived substrates in the left ventricle and red gastrocnemius muscle from rodents, and in human skeletal muscle. When considering intramuscular concentrations of ketone bodies and the presence of other carbohydrate and lipid substrates, biological rates of mitochondrial respiration supported by ketone bodies are predicted to be minimal. At the mitochondrial level, it is therefore unlikely that ketone bodies are an important source for energy production in cardiac and skeletal muscle, particularly when other substrates are readily available.

Ketone bodies (KB) have recently gained popularity as an alternative fuel source to support mitochondrial ntracellular substrates (succinate + palmitoylcarnitine) decreased maximal KB-supported respiration. As a result, product inhibition is likely to limit KB oxidation. Altogether, the ability of KBs to drive mitochondrial respiration is minimal and they are likely to be outcompeted by other substrates, compromising their use as an important energy source.N6 -methyladenosine (m6 A) is a prevalent modification in messenger RNAs and circular RNAs that play important roles in regulating various aspects of RNA metabolism. However, the occurrence of the m6 A modification in plant circular RNAs has not been reported. A widely used method to identify m6 A modifications relies on m6 A-specific antibodies followed by next-generation sequencing of precipitated RNAs (MeRIP-Seq). However, one limitation of MeRIP-Seq is that it does not provide the precise location of m6 A at single-nucleotide resolution. Although more recent sequencing techniques such as Nanopore-based direct RNA sequencing (DRS) can overcome such limitations, the technology does not allow sequencing of circular RNAs, as these molecules lack a poly(A) tail. Here, we developed a novel method to detect the precise location of m6 A modifications in circular RNAs using Nanopore DRS. We first enriched our samples for circular RNAs, which we then fragmented and sequenced on the Nanopore platform with a customized protocol. Using this method, we identified 470 unique circular RNAs from DRS reads based on the back-spliced junction region. Among exonic circular RNAs, about 10% contained m6 A sites, which mainly occurred around acceptor and donor splice sites. This study demonstrates the utility of our antibody-independent method in identifying total and methylated circular RNAs using Nanopore DRS. This method has the additional advantage of providing the exact location of m6 A sites at single-base resolution in circular RNAs or linear transcripts from non-coding RNA without poly(A) tails.We evaluated the association between weight status and motor competence from preschool age (3-5 years of age) until middle childhood (7-9 years of age). Longitudinal study with three to five-year-old preschool children (n=1155) enrolled in public and private preschools in Recife, Brazil. Children were followed twice (2010, 2012 and 2014) for four years. Köperkoordinationstest für kinder (KTK) assessed the children's motor competence (KTK Motor Quotient). Weight status (underweight, normal weight, overweight and obesity) was classified according to the children's sex and age. Preschool children with normal weight exhibited higher motor competence at 5-7 years of age compared to preschool children with overweight (+3.73 MQ, p=0.03) and obesity (+5.09 MQ, p less then 0.01). Preschool children with normal weight presented higher motor competence at 7-9 years of age compared to their peers with overweight (+6.00 MQ, p=0.03) and obesity (+5.88 MQ, p=0.01). Children with normal weight at 5-7 years of age presented higher motor competence at 7-9 years of age compared to their peers with overweight (+3.33 MQ, p=0.02) and obesity (+4.00 MQ, p=0.02). Independent of the childhood phase and extension of the period evaluated (two-or-four year period), children who had excessive weight (overweight or obesity) and changed their weight status to underweight or normal weight presented similar motor competence compared to children who continued underweight or normal weight. Weight status already at preschool age is an important predictor of the children's motor competence until middle childhood. Interventions improving the children's weight status, already at preschool age, might impact their motor competence development positively.Defect information is critical for both fundamental research and industrial analysis of metals and semiconductors. Diffraction contrast is the basis for defect imaging using either X-ray or electron microscopy. Taking the advantage of high resolution in electron microscopy techniques, here we evaluate the efficiency for diffraction contrast imaging based on scanning transmission electron microscopy. The working principle and application are demonstrated using the typical semiconductor material silicon as an example. The efficiency is improved at least an order of magnitude compared with conventional electron microscopy method.Metallocenes with interlinked cyclopentadienide ligands are commonly referred to as ansa-metallocenes or metallocenophanes. These can have drastically different properties than their unbridged parent compounds. While this concept is best known for transition metals such as iron, it can also be adopted for many main-group elements. This review aims to summarize recent advances in the field of metallocenophanes based on main-group elements of group 2, group 13, group 14 and group 15, focusing on synthesis, structure and properties of these compounds.The aim of the present study is to determine four anionic alkyl sulfate (AS) surfactants with different alkyl chains, namely, C8, C10, C12, and C14, in wastewater by CE with capacitively coupled contactless conductivity detection (CE-C4 D). The conditions effective for the separation of the four AS surfactants were systematically optimized and found to be in a Tris-His (50 mM/20 mM) BGE solution at a pH of 8.95, using a separation voltage of +15 kV, hydrodynamic injection by siphoning using a 20 cm injection height and an injection time of 20 s. The LODs for C8, C10, C12, and C14 were 2.58, 2.30, 2.08, and 3.16 mg/L, respectively. The conditions used to achieve the simultaneous adsorption and preconcentration of the AS surfactants using Al2 O3 beads were pH of 3 and 0.1 mM NaCl. The adsorption efficiencies were found to be 45.6, 50.8, 81.7, and 99.9%, while the desorption efficiencies reached 66.1, 70.4, 83.9, and 100.0% for C8, C10, C12, and C14, respectively. The concentrations of the AS surfactants in wastewater samples were quantified by CE-C4 D after preconcentration by simultaneous adsorption using Al2 O3 beads. The results obtained from the proposed method were consistent with those obtained by HPLC-MS/MS, with a deviation of less than 15%. Our results indicate that the CE-C4 D performed after preconcentration by an adsorption technique using Al2 O3 beads is a new, inexpensive, and suitable method for quantifying AS surfactants in wastewater samples.
Small for gestational age (SGA) fetuses have an increased risk for adverse outcome. Placental insufficiency leads to changes in the circulation, with secondary adaptation of the fetal heart resulting in changed cardiac deformation. This deformation can be measured with 2D speckle tracking echocardiography (2D-STE). SGA is antenatally often undiagnosed. The measurement of deformation changes in the fetal heart might help in the prediction of SGA and identify fetuses in need of more intensive surveillance.

In this longitudinal prospective cohort study, global longitudinal strain (GLS) and strain rate (GLSR), measured before 23 weeks gestational age were compared between SGA and appropriate for gestational age (AGA) fetuses, based on birthweight corrected for gestational age at birth.

The fetal heart rate was significantly increased in SGA; 158 beats per minute (146-163) vs 148 (134-156); P = 0.035 in AGA. Right ventricle GLS (RV-GLS) values were significantly increased in SGA; -15.87% (-11.69% to -20.55%) vs -20.24% (-16.29% to -24.28%); p = 0.024, respectively.

RV-GLS values, measured with 2D-STE, were significantly increased in SGA, indicating systolic RV dysfunction before 23 weeks gestational age in fetuses who will become SGA later in pregnancy. A large longitudinal prospective cohort study is needed to confirm these findings.
RV-GLS values, measured with 2D-STE, were significantly increased in SGA, indicating systolic RV dysfunction before 23 weeks gestational age in fetuses who will become SGA later in pregnancy. A large longitudinal prospective cohort study is needed to confirm these findings.Donor-derived cell-free DNA (dd-cfDNA) is a promising biomarker for monitoring allograft status. However, whether dd-cfDNA can reflect real-time anti-rejection treatment effects remains unclear. We prospectively recruited 28 patients with acute renal rejection, including 5 with ABMR, 12 with type IA or type IB rejection, and 11 with type IIA or IIB rejection. dd-cfDNA levels in peripheral blood were measured using human single nucleotide polymorphism (SNP) locus capture hybridization. The percentage of dd-cfDNA (dd-cfDNA%) declined significantly from 2.566 ± 0.549% to 0.773 ± 0.116% (P less then .001) after anti-rejection therapy. The dd-cfDNA% decreased steadily over the course of 3 days with daily methylprednisolone injections, but no significant difference in the dd-cfDNA% was observed between the end of anti-rejection therapy and 2 weeks later. Changes in the dd-cfDNA% (∆dd-cfDNA%) demonstrated a positive correlation with estimated glomerular filtration rates at 1 month (ρ = 2.570, P = .022), 3 months (ρ = 3.210, P = .027), and 6 months (ρ = 2.860, P = .019) after therapy. Thus, the dd-cfDNA assay shows prognostic capabilities in therapy outcome and allograft recovery; however, its ability is inhibited by methylprednisolone regardless of the types of rejection. Additionally, a reassessment of frequency intervals for testing is required.Fracture-related infection (FRI) is a serious complication following musculoskeletal trauma. Accurate diagnosis and appropriate treatment depend on retrieving adequate deep tissue biopsies for bacterial culture. The aim of this cohort study was to compare intraoperative tissue cultures obtained by the Reamer-Irrigator-Aspirator system (RIA)-system against standard tissue cultures obtained during the same surgical procedure. All patients had long bone fractures of the lower limbs and were assigned to the FRI or Control group based on the FRI consensus definition. The FRI group consisted of 24 patients with confirmed FRI and the Control group consisted of 21 patients with aseptic nonunion or chronic pain (in the absence of other suggestive/confirmatory criteria). Standard tissue cultures and cultures harvested by the RIA-system showed similar results. In the FRI group, standard tissue cultures and RIA cultures revealed relevant pathogens in 67% and 71% of patients, respectively. Furthermore, in four FRI patients, cultures obtained by the RIA-system revealed additional relevant pathogens that were not found by standard tissue culturing, which contributed to the optimization of the treatment plan. In the Control group, there were no false-positive RIA culture results. As a proof-of-concept, this cohort study showed that the RIA-system could have a role in the diagnosis of FRI as an adjunct to standard tissue cultures. Since scientific evidence on the added value of the RIA-system in the management of FRI is currently limited, further research on this topic is required before its routine application in clinical practice.Early-phase dose-finding clinical trials are often subject to the issue of late-onset outcomes. In phase I/II clinical trials, the issue becomes more intractable because toxicity and efficacy can be competing risk outcomes such that the occurrence of the first outcome will terminate the other one. In this paper, we propose a novel Bayesian adaptive phase I/II clinical trial design to address the issue of late-onset competing risk outcomes. We use the continuation-ratio model to characterize the trinomial response outcomes and the cause-specific hazard rate method to model the competing-risk survival outcomes. We treat the late-onset outcomes as missing data and develop a Bayesian data augmentation method to impute the missing data from the observations. We also propose an adaptive dose-finding algorithm to allocate patients and identify the optimal biological dose during the trial. Simulation studies show that the proposed design yields desirable operating characteristics.
β-Nicotinamide adenine dinucleotide (β-NAD) is a key inhibitory neurotransmitter in the colon. The neuroeffector junction in the gut consists of enteric motor neurons and SIP syncytium, including smooth muscle cells (SMCs), interstitial cells of Cajal (ICC), and cells expressing platelet-derived growth factor receptor α (PDGFRα
cells). Measuring metabolism of 1,N
-etheno-NAD (eNAD) in colonic tunica muscularis and in SMCs, ICC and PDGFRα
cells with HPLC-FLD, we report that (1) in tissues, eNAD is degraded to eADP-ribose, eAMP and e-adenosine (eADO) by CD38, ENPP1 and NT5E, (2) with SMCs and PDGFRα
cells, eNAD is metabolized to eADO by ENPP1 and NT5E, (3) eNAD is not metabolized by ICC, (4) NT5E is expressed chiefly by SMCs and moderately by PDGFRα
cells, (5) SIP cells are not the primary location of CD38. These data argue that the duration and strength of purinergic neurotransmission can be modulated by targeting multiple enzymes with specialized cellular distribution in the colon.

Prior studiescells using liquid chromatography. eNAD exposed to colonic muscularis of wild-type mice produced eADPR, eAMP and eADO. CD38 mediated the conversion of eNAD to eADPR, whereas ENPP1 mediated degradation of eNAD and eADPR to eAMP. NT5E (aka CD73) was the primary enzyme forming eADO from eAMP. PDGFRα
cells and SMCs were involved in production of eADO from eNAD, and ICC were not involved in extracellular metabolism of eNAD. CD38 mediated the eNAD metabolism in whole tissues, but CD38 did not appear to be functionally expressed by SMCs or ICC. NT5E was expressed in SMCs>PDGFRα
cells. Our data show that extracellular metabolism of β-NAD in the colon is mediated by multiple enzymes with cell-specific expression.
PDGFRα+ cells. Our data show that extracellular metabolism of β-NAD in the colon is mediated by multiple enzymes with cell-specific expression.
Motor units, comprising a motor neuron and the muscle fibre it innervates, are activated in an orderly fashion to provide varying amounts of force. A unilateral C2 spinal hemisection (C2SH) disrupts predominant excitatory input from medulla, causing cessation of inspiratory-related diaphragm muscle activity, whereas higher force, non-ventilatory diaphragm activity persists. In this study, we show a disproportionately larger loss of excitatory glutamatergic innervation to small phrenic motor neurons (PhMNs) following C2SH, as compared with large PhMNs ipsilateral to injury. Our data suggest that there is a dichotomy in the distribution of inspiratory-related descending excitatory glutamatergic input to small vs. large PhMNs that reflects their differential recruitment.

Excitatory glutamatergic input mediating inspiratory drive to phrenic motor neurons (PhMNs) emanates primarily from the ipsilateral ventrolateral medulla. Unilateral C2 hemisection (C2SH) disrupts this excitatory input, resulting in cessatiod premotor neurons in the ventrolateral medulla, sending predominantly ipsilateral projections via the dorsolateral funiculus. C2SH disrupts this glutamatergic input. For larger PhMNs, a large proportion of excitatory inputs appear to exist below the C2 level or from contralateral regions of the brainstem and spinal cord.A mathematical model and a possible neural mechanism are proposed to account for how fixational drift motion in the retina confers a benefit for the discrimination of high-acuity targets. We show that by simultaneously estimating object shape and eye motion, neurons in visual cortex can compute a higher quality representation of an object by averaging out non-uniformities in the retinal sampling lattice. The model proposes that this is accomplished by two separate populations of cortical neurons - one providing a representation of object shape and another representing eye position or motion - which are coupled through specific multiplicative connections. Combined with recent experimental findings, our model suggests that the visual system may utilize principles not unlike those used in computational imaging for achieving "super-resolution" via camera motion.The depth and extent of interocular suppression were measured in binocularly normal observers who unilaterally adapted to neutral density (ND) filters (0, 1.5, 2, and 3 ND). Suppression was measured by dichoptically matching sectors of a ring presented to the adapted eye to a fixed contrast contiguous ring presented to the non-adapted eye. Other rings of alternating polarity were viewed binocularly. Rings were defined by luminance (L), luminance with added dynamic binary luminance noise (LM), and contrast modulating the same noise (CM). Interocular suppression depth increased with increasing ND, nearing significance (p = 0.058) for 1.5 ND. For L and LM stimuli, suppression depth across eccentricity (±12° visual field) differed for luminance increment (white) versus luminance decrement (black) stimuli, potentially confounding eccentricity results. Suppression for increment-only (white) luminance stimuli was steeper centrally and extended across the visual field, but was deeper for L than for LM stimuli. Suppression for decrement-only (black) luminance stimuli revealed only central suppression. Suppression was deeper with CM than LM stimuli, suggesting that CM stimuli are extracted in areas receiving predominantly binocular input which may be more sensitive to binocular disruption. Increment (white) luminance stimuli demonstrate deeper interocular suppression in the periphery than decrement (black) stimuli, so they are more sensitive to changes in peripheral suppression. Asymmetry of suppression in the periphery for opposite polarity luminance stimuli may be due to interocular receptive field size mismatch as a result of dark adaptation separately affecting ON and OFF pathways. Clinically, measurement of suppression with CM stimuli may provide the best information about post-combination binocularity.Although formaldehyde is a normal constituent of tissues, lifetime inhalation exposures at 6 h/day, 5 days/week at concentrations ≥6 ppm caused a nonlinear increase in nasal tumors in rats with incidence reaching close to 50% at 15 ppm. Studies with heavy isotope labeled [13CD2]-formaldehyde permit quantification of both the mass-labeled exogenous and endogenous DNA-formaldehyde reaction products. An existing pharmacokinetic model developed initially to describe 14C-DNA-protein crosslinks (DPX) provided a template for describing the time course of mass-labeled adducts. Published datasets included both DPX and N2-HO13CD2-dG adducts measured after a single 6-h exposure to 0.7, 2, 6, 9, 10, or 15 ppm formaldehyde, after multi-day exposures to 2 ppm for 6 h/day, 7 days/week with interim sacrifices up to 28 days, and after 28-day exposures for 6 h/day, 7 days/week to 0.3, 0.03, or 0.001 ppm. The existing kinetic model overpredicted endogenous adducts in the nasal epithelium after 1-day [13CD2]-formaldehyde exposure, requiring adjustment of parameters for rates of tissue metabolism and background formaldehyde. After refining tissue formaldehyde parameters, we fit the model to both forms of adducts by varying key parameters and optimizing against all 3 studies. Fitting to all these studies required 2 nonlinear pathways-one for high-exposure saturation of clearance in the nasal epithelial tissues and another for extracellular clearance that restricts uptake into the epithelial tissue for inhaled concentrations below 0.7 ppm. This refined pharmacokinetic model for endogenous and exogenous formaldehyde acetal adducts can assist in updating biologically based dose-response models for formaldehyde carcinogenicity.
The coronavirus disease 2019 (COVID-19) pandemic poses an existential threat to many US residential colleges; either they open their doors to students in September or they risk serious financial consequences.

To define severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) screening performance standards that would permit the safe return of students to US residential college campuses for the fall 2020 semester.

This analytic modeling study included a hypothetical cohort of 4990 students without SARS-CoV-2 infection and 10 with undetected, asymptomatic SARS-CoV-2 infection at the start of the semester. The decision and cost-effectiveness analyses were linked to a compartmental epidemic model to evaluate symptom-based screening and tests of varying frequency (ie, every 1, 2, 3, and 7 days), sensitivity (ie, 70%-99%), specificity (ie, 98%-99.7%), and cost (ie, $10/test-$50/test). Reproductive numbers (Rt) were 1.5, 2.5, and 3.5, defining 3 epidemic scenarios, with additional infections imported via ehavioral interventions to keep Rt less than 2.5, is estimated to maintain a controllable number of COVID-19 infections and permit the safe return of students to campus.
Evidence-based care plans can fail when they do not consider relevant patient life circumstances, termed contextual factors, such as a loss of social support or financial hardship. Preventing these contextual errors can reduce obstacles to effective care.

To evaluate the effectiveness of a quality improvement program in which clinicians receive ongoing feedback on their attention to patient contextual factors.

In this quality improvement study, patients at 6 Department of Veterans Affairs outpatient facilities audio recorded their primary care visits from May 2017 to May 2019. Encounters were analyzed using the Content Coding for Contextualization of Care (4C) method. A feedback intervention based on the 4C coded analysis was introduced using a stepped wedge design. In the 4C coding schema, clues that patients are struggling with contextual factors are termed contextual red flags (eg, sudden loss of control of a chronic condition), and a positive outcome is prospectively defined for each encounter as a at a cost of $337 242 for the intervention.

These findings suggest that patient-collected audio recordings of the medical encounter with feedback may enhance clinician attention to contextual factors, improve outcomes, and reduce hospitalizations. In addition, the intervention is associated with substantial cost savings.
These findings suggest that patient-collected audio recordings of the medical encounter with feedback may enhance clinician attention to contextual factors, improve outcomes, and reduce hospitalizations. In addition, the intervention is associated with substantial cost savings.
Obtaining informed consent is an important ethical obligation for clinical research participation that is imperfectly implemented. Research on improving consent processes often focuses on consent forms, but little is known about consent forms' influence on decision-making compared with other types of engagement.

To evaluate whether parents decide whether to enroll their children in research before or after they receive the consent form.

An online survey of 88 parents who enrolled or declined to enroll their child in a weight management intervention study between January 2, 2018, and June 24, 2019, was conducted; surveys were completed between February 2, 2018, and July 9, 2019. A 31-item survey asked about impressions of the study throughout the enrollment process, timing of enrollment decisions, and decision-making factors. Responses were summarized descriptively and subgroups were compared using the Fisher exact test or χ2 test.

Self-reported timing of enrollment decision.

A total of 106 parents ws to improve informed consent forms may have limited influence on decision-making because many research decisions occur before review of the consent form. It appears that regulatory review and interventions to improve decision-making should focus more on early engagement (eg, recruitment materials). Future studies should test timing of decisions in other types of research with different populations and clinical settings.
The findings of this study suggest that interventions to improve informed consent forms may have limited influence on decision-making because many research decisions occur before review of the consent form. It appears that regulatory review and interventions to improve decision-making should focus more on early engagement (eg, recruitment materials). Future studies should test timing of decisions in other types of research with different populations and clinical settings.
Postoperative neurocognitive disorders (PNDs) after surgical procedures are common and may be associated with increased health care expenditures.

To quantify the economic burden associated with a PND diagnosis in 1 year following surgical treatment among older patients in the United States.

This retrospective cohort study used claims data from the Bundled Payments for Care Improvement Advanced Model from 4285 hospitals that submitted Medicare Fee-for-service (FFS) claims between January 2013 and December 2016. All Medicare patients aged 65 years or older who underwent an inpatient hospital admission associated with a surgical procedure, did not experience a PND before index admission, and were not undergoing dialysis or concurrently enrolled in Medicaid were included. Data were analyzed from October 2019 and May 2020.

PND, defined as an International Classification of Diseases, Ninth or Tenth Revision, diagnosis of delirium, mild cognitive impairment, or dementia within 1 year of discharge from the inusting for patient and hospital characteristics, the presence of a PND within 1 year of the index procedure was associated with an increase of $17 275 (95% CI, $17 058-$17 491) in cost in the 1-year postadmission period (P < .001).

The findings of this cohort study suggest that among older Medicare patients undergoing surgical treatment, a diagnosis of a PND was associated with an increase in health care costs for up to 1 year following the surgical procedure. Given the magnitude of this cost burden, PNDs represent an appealing target for risk mitigation and improvement in value-based health care.
The findings of this cohort study suggest that among older Medicare patients undergoing surgical treatment, a diagnosis of a PND was associated with an increase in health care costs for up to 1 year following the surgical procedure. Given the magnitude of this cost burden, PNDs represent an appealing target for risk mitigation and improvement in value-based health care.
A substantial proportion of parents whose child is diagnosed with a life-threatening illness experience high levels of distress that can lead to long-term mental health difficulties. This can affect the child's recovery.

To evaluate the efficacy of an acceptance and commitment therapy-based group intervention, delivered using videoconferencing, in reducing posttraumatic stress symptoms (PTSS) in these parents.

This study was a randomized clinical trial of an intervention for parents with elevated acute stress symptoms. It was a single-site study conducted in a tertiary pediatric hospital in Australia. Parents of children aged 0 to 18 years admitted for a life-threatening illness or injury to the oncology, cardiology, or pediatric intensive care departments were eligible. Participants were screened for eligibility within the first month after diagnosis or admission and then were randomized to the intervention group or the waiting list control group 4 to 10 months after diagnosis or admission. Recruitmentm 23.3 (95% CI, 18.6-28.1) to 17.8 (95% CI, 13.8-21.8) in the intervention group.

The findings of this study support the use of acceptance and commitment therapy to reduce PTSS in parents of very ill children, regardless of diagnosis. These findings also suggest that a brief, group format using a videoconferencing platform can be used effectively to access hard-to-reach populations, particularly fathers and caregivers living in nonmetropolitan areas.

Australian New Zealand Clinical Trials Registry Identifier ACTRN12611000090910.
Australian New Zealand Clinical Trials Registry Identifier ACTRN12611000090910.
Age-related sensory loss and frailty are common conditions among older adults, but epidemiologic research on their possible links has been inconclusive. Clarifying this relationship is important because sensory loss may be a clinically relevant risk factor for frailty.

In this systematic review and meta-analysis, we searched 3 databases for observational studies investigating 4 sensory impairments-vision (VI), hearing (HI), smell (SI), and taste (TI)-and their relationships with frailty. We meta-analyzed the cross-sectional associations of VI/HI each with pre-frailty and frailty, investigated sources of heterogeneity using meta-regression and subgroup analyses, and assessed publication bias using Egger's test.

We included 17 cross-sectional and 7 longitudinal studies in our review (N = 34,085) from 766 records. Our cross-sectional meta-analyses found that HI and VI were, respectively, associated with 1.5- to 2-fold greater odds of pre-frailty and 2.5- to 3-fold greater odds of frailty. Our results remaimodifiability of these relationships and the impact of SI/TI and multiple sensory impairments on frailty.
In mammalian ventricles, electrical gradients establish electrical heterogeneities as essential tissue mechanisms to optimize mechanical efficiency and safeguard electrical stability. Electrical gradients shape mammalian electrocardiographic patterns; disturbance of electrical gradients is proarrhythmic. The zebrafish heart is a popular surrogate model for human cardiac electrophysiology thanks to its remarkable recapitulation of human electrocardiogram and ventricular action potential features. Yet, zebrafish ventricular electrical gradients are largely unexplored. The goal of this study is to define the zebrafish ventricular electrical gradients that shape the QRS complex and T wave patterns at baseline and under oxidative stress.

We performed in vivo electrocardiography and ex vivo voltage-sensitive fluorescent epicardial and transmural optical mapping of adult zebrafish hearts at baseline and during acute H2O2 exposure. At baseline, apicobasal activation and basoapical repolarization gradients accountions of the adult zebrafish heart as model for mammalian arrhythmogenesis studies.
Zebrafish electrocardiograms remarkably recapitulate human electrocardiograms in health and disease. Yet, the underlying tissue mechanisms were unknown. This study provides the first demonstration that the baseline electrical gradients that shape zebrafish ventricular electrocardiograms are opposite human electrical gradients. Additionally, like mammalian hearts, zebrafish hearts are susceptible to CaMKII-mediated H2O2 proarrhythmic perturbations. Despite its vital role in zebrafish cardiac regeneration following injury, H2O2 can disrupt zebrafish sinus node activity, cause all three types of atrioventricular blocks, and reverse ventricular electrical gradients. These findings highlight the clinical relevance, utility, and limitations of the adult zebrafish heart as model for mammalian arrhythmogenesis studies.Species within the mint family, Lamiaceae, are widely used for their culinary, cultural, and medicinal properties due to production of a wide variety of specialized metabolites, especially terpenoids. To further our understanding of genome diversity in the Lamiaceae and to provide a resource for mining biochemical pathways, we generated high-quality genome assemblies of four economically important culinary herbs, namely, sweet basil (Ocimum basilicum L.), sweet marjoram (Origanum majorana L.), oregano (Origanum vulgare L.), and rosemary (Rosmarinus officinalis L.), and characterized their terpenoid diversity through metabolite profiling and genomic analyses. A total 25 monoterpenes and 11 sesquiterpenes were identified in leaf tissue from the 4 species. Genes encoding enzymes responsible for the biosynthesis of precursors for mono- and sesqui-terpene synthases were identified in all four species. Across all 4 species, a total of 235 terpene synthases were identified, ranging from 27 in O. majorana to 137 in the tetraploid O. basilicum. This study provides valuable resources for further investigation of the genetic basis of chemodiversity in these important culinary herbs.COVID-19 abruptly halted scientific conferences and seminars in mid-March, forcing the scientific community to either postpone or adapt to a virtual format. We caught up with Carla V. Rothlin, Elina I. Zúñiga, Hongbo Chi, Rino Rappuoli, and Matthew Krummel to find out about the pros and cons of virtual conferences and seminars and how these could change the nature of scientific conferences. Carla (CVR) and Elina (EIZ) established Global ImmunoTalks in April this year; Hongbo (HC) helped organize the Immunometabolism Mini-Symposia series in May and June; Rino (RR) was one of the scientific organizers of the Transforming Vaccinology Keystone, which moved to a virtual format in June; and Matthew (MK) has been organizing Eco Seminars at the University of California, San Francisco since 2019.Vitamin D deficiency is a pandemic disorder affecting over 1 billion of subjects worldwide and displaying a broad spectrum of implications on cardiovascular and inflammatory disorders. Since the initial reports of the association between hypovitaminosis D and COVID-19, Vitamin D has been pointed as a potentially interesting treatment for SARS-CoV-2 infection. We provide an overview on the current status of vitamin D deficiency, the mechanisms of action of vitamin D and the current literature on the topic, with a special focus on the potential implications for COVID-19 pandemic.
To quantitatively demonstrate asymmetric choroidal outflow in pachychoroid (central serous chorioretinopathy [CSC]/pachychoroid pigment epitheliopathy [PPE]) eyes using mid-phase, ultra-widefield indocyanine green angiography (UWF ICGA) images.

Eyes with a clinical diagnosis of CSC/PPE were imaged with multimodal imaging including UWF ICGA (Optos California). Quadrant brightness was measured by manually segmenting based on vortex vein location, calculating the brightness "max-min" value to assess nonuniformity between quadrants, and comparing between CSC/PPE and control eyes. A multivariate linear regression was performed to determine, across individual eyes, which specific quadrants have the greatest brightness in pachychoroid eyes, after taking into account patient-eye-specific variability.

Thirty-three eyes (18 patients) with CSC/PPE along with 16 eyes of 9 controls had a mean age of 51.94 ± 9.72 vs. 53.78 ± 17.92 years (P = 0.731), respectively. Max-min analysis showed significantly increased likelis in mid-phase ICGA images suggest venous outflow congestion among eyes with CSC or PPE.
We sought to determine the role of glycogen synthase kinase-3β (GSK-3β) in the pathogenesis of Graves' orbitopathy(GO).

Expression of the GSK-3β gene in whole orbital tissue explants was compared between GO and non-GO donors using quantitative real-time PCR (RT-PCR). The expression of proinflammatory molecules in the presence of the GSK-3β inhibitor CHIR 99021 was analyzed using RT-PCR, western blot, and ELISA. Adipogenic differentiation was identified using Oil Red O staining, and the levels of peroxisome proliferator activator gamma (PPARγ) and CCAAT-enhancer-binding proteins (C/EBPs) α and β were determined by western blot.

The expression of GSK-3β was significantly higher in GO tissues than in control tissues. The addition of CHIR 99021 led to a decrease in the active form of the kinase in which the Y216 residue is phosphorylated. When GO and non-GO fibroblasts were stimulated with IL-1β or TNF-α, IL-6, IL-8, intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-1 (COX-1), and monocyte chemoattractant protein 1 (MCP-1) showed increased production, which was blunted when CHIR 99021 was added. The activation of Akt, PI3K, nuclear factor (NF)-κB, Erk, Jnk, and p38 kinase by IL-1β and TNF-α was diminished with CHIR 99021 in GO cells. A decrease in lipid droplets and expression of PPARγ and c/EBPα and -β was noted in fibroblasts treated with CHIR 99021 during adipocyte differentiation. The inhibition of Wnt and β-catenin in adipogenesis was reversed by CHIR 99021.

GSK-3β plays a significant role in GO pathogenesis. The inhibition of the kinase attenuated the proinflammatory cytokines production and fibroblast differentiation into adipocytes. GSK-3β may be a potential target for anti-inflammatory and anti-adipogenic treatment of GO.
GSK-3β plays a significant role in GO pathogenesis. The inhibition of the kinase attenuated the proinflammatory cytokines production and fibroblast differentiation into adipocytes. GSK-3β may be a potential target for anti-inflammatory and anti-adipogenic treatment of GO.
Leber hereditary optic neuropathy (LHON) is a genetic form of vision loss that occurs primarily owing to mutations in the nicotinamide adenine dinucleotide dehydrogenase (ND) subunits that make up complex I of the electron transport chain. LHON mutations result in the apoptotic death of retinal ganglion cells. We tested the hypothesis that gene therapy with the X-linked inhibitor of apoptosis (XIAP) would prevent retinal ganglion cell apoptosis and reduce disease progression in a vector-induced mouse model of LHON that carries the ND4 mutation.

Adeno-associated virus (AAV) encoding full length hemagglutinin-tagged XIAP (AAV2.HA-XIAP) or green fluorescent protein (AAV2.GFP) was injected into the vitreous of DBA/1J mice. Two weeks later, the LHON phenotype was induced by AAV delivery of mutant ND4 (AAV2.mND4FLAG) to the vitreous. Retinal function was assessed by pattern electroretinography. Optic nerves were harvested at 4 months, and the effects of XIAP therapy on nerve fiber layer and optic nerve integrity were evaluated using immunohistochemistry, transmission electron microscopy and magnetic resonance imaging.

During LHON disease progression, retinal ganglion cell axons are lost. Apoptotic cell bodies are seen in the nuclei of astrocytes or oligodendrocytes in the optic nerve, and there is thinning of the optic nerve and the nerve fiber layer of the retina. At 4 months after disease onset, XIAP gene therapy protects the nerve fiber layer and optic nerve architecture by preserving axon health. XIAP also decreases nuclear fragmentation in resident astrocytes or oligodendrocytes and decreases glial cell infiltration.

XIAP therapy improves optic nerve health and delays disease progression in LHON.
XIAP therapy improves optic nerve health and delays disease progression in LHON.
The searching of user-defined 3D queries in molecular interfaces is a computationally challenging problem that is not satisfactorily solved so far. Most of the few existing tools focused on that purpose are desktop based and not openly available. Besides that, they show a lack of query versatility, search efficiency, and user-friendliness. We address this issue with GeoMine, a publicly available web application that provides textual, numerical, and geometrical search functionality for protein-ligand binding sites derived from structural data contained in the PDB. The query generation is supported by a 3D representation of a start structure that provides interactively selectable elements like atoms, bonds, and interactions. GeoMine gives full control over geometric variability in the query while performing a deterministic, precise search. Reasonably selective queries are processed on the entire set of protein-ligand complexes in the PDB within a few minutes.

GeoMine offers an interactive and iterative search process of successive result analyses and query adaptations.
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