Multimodality assessment of the coronary microvasculature with TIMI frame count versus perfusion PET highlights coronary changes characteristic of coronary microvascular disease.

Background: The diagnosis of coronary microvascular disease (CMVD) remains challenging. Perfusion PET-derived myocardial blood flow (MBF) reserve (MBFR) can quantify CMVD but is not widely available. Thrombolysis in Myocardial Infarction (TIMI) frame count (TFC) is an angiography-based method that has been proposed as a measure of CMVD. Here, we compare TFC and PET-derived MBF measurements to establish the role of TFC in assessing for CMVD. We use coronary modeling to elucidate the relationship between MBFR and TFC and propose TFC thresholds for identifying CMVD. Methods: In a cohort of 123 individuals (age 58 ± 12.1, 63% women, 41% Caucasian) without obstructive coronary artery disease who had undergone perfusion PET and coronary angiography for clinical indications, we compared TFC and perfusion PET parameters using Pearson correlation (PCC) and linear regression modeling. We used mathematical modeling of the coronary circulation to understand the relationship between these parameters and performed Receiver Operating Curve (ROC) analysis. Results: We found a significant negative correlation between TFC and MBFR. Sex, race and ethnicity, and nitroglycerin administration impact this relationship. Coronary modeling showed an uncoupling between TFC and flow in epicardial vessels. In ROC analysis, TFC performed well in women (AUC 0.84-0.89) and a moderately in men (AUC 0.68-0.78). Conclusions: We established an inverse relationship between TFC and PET-derived MBFR, which is affected by patient selection and procedural factors. TFC represents a measure of the volume of the epicardial coronary compartment, which is increased in patients with CMVD, and performs well in identifying women with CMVD.

Neuroanatomical dimensions in medication-free individuals with major depressive disorder and treatment response to SSRI antidepressant medications or placebo.

Major depressive disorder (MDD) is a heterogeneous clinical syndrome with widespread subtle neuroanatomical correlates. Our objective was to identify the neuroanatomical dimensions that characterize MDD and predict treatment response to selective serotonin reuptake inhibitor (SSRI) antidepressants or placebo. In the COORDINATE-MDD consortium, raw MRI data were shared from international samples (N = 1,384) of medication-free individuals with first-episode and recurrent MDD (N = 685) in a current depressive episode of at least moderate severity, but not treatment-resistant depression, as well as healthy controls (N = 699). Prospective longitudinal data on treatment response were available for a subset of MDD individuals (N = 359). Treatments were either SSRI antidepressant medication (escitalopram, citalopram, sertraline) or placebo. Multi-center MRI data were harmonized, and HYDRA, a semi-supervised machine-learning clustering algorithm, was utilized to identify patterns in regional brain volumes that are associated with disease. MDD was optimally characterized by two neuroanatomical dimensions that exhibited distinct treatment responses to placebo and SSRI antidepressant medications. Dimension 1 was characterized by preserved gray and white matter (N = 290 MDD), whereas Dimension 2 was characterized by widespread subtle reductions in gray and white matter (N = 395 MDD) relative to healthy controls. Although there were no significant differences in age of onset, years of illness, number of episodes, or duration of current episode between dimensions, there was a significant interaction effect between dimensions and treatment response. Dimension 1 showed a significant improvement in depressive symptoms following treatment with SSRI medication (51.1%) but limited changes following placebo (28.6%). By contrast, Dimension 2 showed comparable improvements to either SSRI (46.9%) or placebo (42.2%) (ß = -18.3, 95% CI (-34.3 to -2.3), P = 0.03). Findings from this case-control study indicate that neuroimaging-based markers can help identify the disease-based dimensions that constitute MDD and predict treatment response.

Validation of fungicide spray strategies and selection for fenhexamid resistance in Botrytis cinerea on greenhouse-grown grapevines.

In this study, in planta assays were conducted to assess the effects of fungicide spray tactics, such as the reduction of the labeled fungicide dose and mixture with a multi-site fungicide, on fungicide resistance selection and disease control using Vitis vinifera 'Cabernet Sauvignon' grown in a greenhouse for two years. The entire clusters were inoculated with B. cinerea isolates at varying frequencies of fenhexamid resistance, followed by fungicide sprays, disease and fenhexamid resistance investigations at critical phenological stages. Our findings indicate that the lower dose of the at-risk fungicide, fenhexamid, effectively managed fenhexamid resistance and disease as well as the higher, labeled dose. In addition, mixture with the multi-site fungicide captan generally resulted a net-positive effect on both resistance management and disease control.

Capturing the Effects of Single Atom Substitutions on the Inhibition Efficiency of Glycogen Synthase Kinase-3ß Inhibitors via Markov State Modeling and Experiments.

Small modifications in the chemical structure of ligands are known to dramatically change their ability to inhibit the activity of a protein. Unraveling the mechanisms that govern these dramatic changes requires scrutinizing the dynamics of protein-ligand binding and unbinding at the atomic level. As an exemplary case, we have studied Glycogen Synthase Kinase-3ß (GSK-3ß), a multifunctional kinase that has been implicated in a host of pathological processes. As such, there is a keen interest in identifying ligands that inhibit GSK-3ß activity. One family of compounds that are highly selective and potent inhibitors of GSK-3ß is exemplified by a molecule termed COB-187. COB-187 consists of a five-member heterocyclic ring with a thione at C2, a pyridine substituted methyl at N3, and a hydroxyl and phenyl at C4. We have studied the inhibition of GSK-3ß by COB-187-related ligands that differ in a single heavy atom from each other (either in the location of nitrogen in their pyridine ring, or with the pyridine ring replaced by a phenyl ring), or in the length of the alkyl group joining the pyridine and the N3. The inhibition experiments show a large range of half-maximal inhibitory concentration (IC50) values from 10 nM to 10 µM, implying that these ligands exhibit vastly different propensities to inhibit GSK-3ß. To explain these differences, we perform Markov State Modeling (MSM) using fully atomistic simulations. Our MSM results are in excellent agreement with the experiments in that they accurately capture differences in the binding propensities of the ligands. The simulations show that the binding propensities are related to the ligands' ability to attain a compact conformation where their two aromatic rings are spatially close. We rationalize this result by sampling numerous binding and unbinding events via funnel metadynamics simulations, which show that indeed while approaching the bound state, the ligands prefer to be in their compact conformation. We find that the presence of nitrogen in the aromatic ring increases the probability of attaining the compact conformation. Protein-ligand binding is understood to be dictated by the energetics of interactions and entropic factors, like the release of bound water from the binding pockets. This work shows that changes in the conformational distribution of ligands due to atom-level modifications in the structure play an important role in protein-ligand binding.

Microscale Diffractive Lenses Integrated into Microfluidic Devices for Size-Selective Optical Trapping of Particles.

Integration of optical components into microfluidic devices can enhance particle manipulations, separations, and analyses. We present a method to fabricate microscale diffractive lenses composed of aperiodically spaced concentric rings milled into a thin metal film to precisely position optical tweezers within microfluidic channels. Integrated thin-film microlenses perform the laser focusing required to generate sufficient optical forces to trap particles without significant off-device beam manipulation. Moreover, the ability to trap particles with unfocused laser light allows multiple optical traps to be powered simultaneously by a single input laser. We have optically trapped polystyrene particles with diameters of 0.5, 1, 2, and 4 µm over microlenses fabricated in chromium and gold films. Optical forces generated by these microlenses captured particles traveling at fluid velocities up to 64 µm/s. Quantitative trapping experiments with particles in microfluidic flow demonstrate size-based differential trapping of neutrally buoyant particles where larger particles required a stronger trapping force. The optical forces on these particles are identical to traditional optical traps, but the addition of a continuous viscous drag force from the microfluidic flow introduces tunable size selectivity across a range of laser powers and fluid velocities.

The stem cell niche transcription factor ETHYLENE RESPONSE FACTOR 115 participates in aluminum-induced terminal differentiation in Arabidopsis roots.

Aluminum-dependent stoppage of root growth requires the DNA damage response (DDR) pathway including the p53-like transcription factor SUPPRESSOR OF GAMMA RADIATION 1 (SOG1), which promotes terminal differentiation of the root tip in response to Al dependent cell death. Transcriptomic analyses identified Al-induced SOG1-regulated targets as candidate mediators of this growth arrest. Analysis of these factors either as loss-of-function mutants or by overexpression in the als3-1 background shows ERF115, which is a key transcription factor that in other scenarios is rate-limiting for damaged stem cell replenishment, instead participates in transition from an actively growing root to one that has terminally differentiated in response to Al toxicity. This is supported by a loss-of-function erf115 mutant raising the threshold of Al required to promote terminal differentiation of Al hypersensitive als3-1. Consistent with its key role in stoppage of root growth, a putative ERF115 barley ortholog is also upregulated following Al exposure, suggesting a conserved role for this ATR-dependent pathway in Al response. In contrast to other DNA damage agents, these results show that ERF115 and likely related family members are important determinants of terminal differentiation of the root tip following Al exposure and central outputs of the SOG1-mediated pathway in Al response.

Efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes (PIONEER 11): a double-blind, Phase IIIa, randomised trial.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes insufficiently controlled with diet and exercise alone. METHODS: The Peptide Innovation for Early Diabetes Treatment (PIONEER) 11 trial was a double-blind, randomised, Phase IIIa trial conducted across 52 sites in the China region (mainland China and Taiwan), Hungary, Serbia and Ukraine. Eligible participants were ≥18 years (≥20 years in Taiwan), had a diagnosis of type 2 diabetes with HbA1c 53-86 mmol/mol (7.0-10.0%) and were not receiving any glucose-lowering drugs. After a 4-week run-in period in which participants were treated with diet and exercise alone, those who fulfilled the randomisation criteria were randomised (1:1:1:1) using a web-based randomisation system to receive once-daily oral semaglutide 3 mg, 7 mg or 14 mg or placebo for 26 weeks (using a 4-week dose-escalation regimen for the higher doses). Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary and confirmatory secondary endpoints were change from baseline to week 26 in HbA1c and body weight (kg), respectively. Safety was assessed in all participants exposed to at least one dose of the trial product. RESULTS: Between October 2019 and October 2021, a total of 774 participants were screened and 521 participants were randomised to oral semaglutide 3 mg (n=130), 7 mg (n=130), 14 mg (n=130) or placebo (n=131); most participants (92.5%, n=482) completed the trial, with 39 participants prematurely discontinuing treatment. The number of participants contributing to the trial analyses was based on the total number of participants who were randomised at the beginning of the trial. The majority of participants were male (63.7%), and the mean age of participants was 52 years. At baseline, mean HbA1c and body weight were 63 mmol/mol (8.0%) and 79.6 kg, respectively. Oral semaglutide resulted in significantly greater reductions in HbA1c than placebo at week 26 (p<0.001 for all doses). The estimated treatment differences (ETDs [95% CIs]) for oral semaglutide 3 mg, 7 mg and 14 mg vs placebo were -11 (-13, -9) mmol/mol, -16 (-18, -13) mmol/mol and -17 (-19, -15) mmol/mol, respectively. The corresponding ETDs in percentage points (95% CI) vs placebo were -1.0 (-1.2, -0.8), -1.4 (-1.6, -1.2) and -1.5 (-1.8, -1.3), respectively. Significantly greater reductions in body weight were also observed for oral semaglutide 7 mg and 14 mg than for placebo at week 26 (ETD [95% CI] -1.2 kg [-2.0 kg, -0.4 kg; p<0.01] and -2.0 kg [-2.8 kg, -1.2 kg; p<0.001], respectively), but not for oral semaglutide 3 mg (ETD [95% CI] -0.0 kg [-0.9 kg, 0.8 kg; not significant]). Similar reductions in HbA1c and body weight were observed in the Chinese subpopulation, which represented 74.9% of participants in the overall population. Adverse events (AEs) occurred in between 65.4% and 72.3% of participants receiving oral semaglutide (for all doses) and 57.3% of participants with placebo. Most AEs were mild to moderate in severity, with few serious AEs reported; the most commonly reported AEs were gastrointestinal-related and were more frequent with semaglutide (all doses) than with placebo. The proportion of AEs was slightly higher in the Chinese subpopulation. CONCLUSIONS/INTERPRETATION: Oral semaglutide resulted in significantly greater reductions in HbA1c across all doses and in significant body weight reductions for the 7 mg and 14 mg doses when compared with placebo in predominantly Chinese participants with type 2 diabetes insufficiently controlled by diet and exercise alone. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04109547. FUNDING: Novo Nordisk A/S.

Efficacy and safety of oral semaglutide vs sitagliptin in a predominantly Chinese population with type 2 diabetes uncontrolled with metformin: PIONEER 12, a double-blind, Phase IIIa, randomised trial.

AIMS/HYPOTHESIS: The aim of this study was to assess the efficacy and safety of oral semaglutide vs sitagliptin in a predominantly Chinese population with type 2 diabetes inadequately controlled with metformin treatment. METHODS: The Peptide Innovation for Early Diabetes Treatment (PIONEER) 12 trial was a randomised, double-dummy, active-controlled, parallel-group, Phase IIIa trial conducted over 26 weeks at 90 sites across the China region (including mainland China, Taiwan and Hong Kong) and five other countries. Adults aged ≥18 years (≥20 years in Taiwan) with a diagnosis of type 2 diabetes, HbA1c between 53 and 91 mmol/mol (inclusive) and treated with a stable daily dose of metformin were eligible for inclusion. Participants were randomised (1:1:1:1) using a web-based randomisation system to either once-daily oral semaglutide (3 mg, 7 mg or 14 mg) or once-daily oral sitagliptin 100 mg. Treatment allocation was masked to both participants and investigators. Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary endpoint was change in HbA1c from baseline to week 26. The confirmatory secondary endpoint was change in body weight (kg) from baseline to week 26. All randomised participants were included in the full analysis set (FAS). All participants exposed to at least one dose of trial product were included in the safety analysis (SAS). RESULTS: Of 1839 participants screened, 1441 were randomly assigned to oral semaglutide 3 mg (n=361), 7 mg (n=360), 14 mg (n=361) or sitagliptin 100 mg (n=359) and included in the FAS. A total of 1438 participants were included in the SAS. In total, 75.2% of participants were from the China region. A total of 1372 (95.2%) participants completed the trial and 130 participants prematurely discontinued treatment (8.3%, 8.6% and 15.0% for oral semaglutide 3 mg, 7 mg and 14 mg, respectively; 4.2% for sitagliptin 100 mg). Significantly greater reductions in HbA1c from baseline to week 26 were reported for all doses of oral semaglutide vs sitagliptin 100 mg. For oral semaglutide 3 mg, 7 mg and 14 mg vs sitagliptin 100 mg, the estimated treatment differences (ETDs [95% CI]) were -2 (-4, -1) mmol/mol, -8 (-9, -6) mmol/mol and -11 (-12, -9) mmol/mol, respectively. The corresponding ETDs (95% CI) in percentage points vs sitagliptin 100 mg were -0.2 (-0.3, -0.1), -0.7 (-0.8, -0.6) and -1.0 (-1.1, -0.8), respectively. Reductions in body weight were significantly greater for all doses of oral semaglutide vs sitagliptin 100 mg (ETD [95% CI] -0.9 [-1.4, -0.4] kg, -2.3 [-2.8, -1.8] kg and -3.3 [-3.8, -2.8] kg for 3 mg, 7 mg and 14 mg, respectively). In the subpopulation of participants from the China region (75.2% of trial participants), reductions in HbA1c and body weight from baseline to week 26 were similar to those seen in the overall population. The most frequent adverse events in the semaglutide treatment arms were gastrointestinal, although these were mostly transient and mild/moderate in severity. CONCLUSIONS/INTERPRETATION: Significantly greater reductions in both HbA1c and body weight over 26 weeks were seen with oral semaglutide 3 mg, 7 mg and 14 mg than with sitagliptin 100 mg in a predominantly Chinese population with type 2 diabetes inadequately controlled with metformin treatment. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04017832. FUNDING: This trial was funded by Novo Nordisk A/S, Søborg, Denmark.

Renovascular Disease and Mitochondrial Dysfunction in Human Mesenchymal Stem Cells.

BACKGROUND: Renovascular disease leads to renal ischemia, hypertension, and eventual kidney failure. Autologous transplantation of adipose tissue-derived mesenchymal stem/stromal cells (MSCs) improves perfusion and oxygenation in stenotic human kidneys, but associated atherosclerosis and hypertension might blunt their effectiveness. We hypothesized that renovascular disease alters the human MSC transcriptome and impairs their reparative potency. METHODS: MSCs were harvested from subcutaneous abdominal fat of renovascular disease patients and healthy volunteers (n=3 each), characterized and subsequently injected (5x10^5/200µL) into mice 2 weeks after renal artery stenosis or sham surgery (n=6/group). Two weeks later, mice underwent imaging and tissue studies. Healthy volunteer- and renovascular disease-MSCs were also characterized by mRNA/microRNA (miRNA)-sequencing. Based on these, MSC proliferation and mitochondrial damage were assessed in-vitro before and after miRNA modulation, and in-vivo in additional renal artery stenosis mice administered with renovascular disease-MSCs pre-treated with miR-378h mimic (n=5) or inhibitor (n=4). RESULTS: MSCs engrafted in stenotic mouse kidneys. Healthy volunteer-MSCs (but not renovascular disease-MSCs) decreased blood pressure, improved serum creatinine levels and stenotic-kidney cortical perfusion and oxygenation, and attenuated peritubular capillary loss, tubular injury, and fibrosis. Genes upregulated in renovascular disease-MSCs versus healthy volunteer-MSCs were mostly implicated in transcription and cell proliferation, whereas those downregulated encoded mainly mitochondrial proteins. Upregulated miRNAs, including miR-378h, primarily target nuclear-encoded mitochondrial genes, whereas downregulated miRNAs mainly target genes implicated in transcription and cell proliferation. MSC proliferation was similar, but their mitochondrial structure and reparative function both in vivo and in vitro improved after miR-378h inhibition. CONCLUSIONS: Renovascular disease impaired the reparative capacity of human MSCs, possibly by dysregulating miR-378h that targets mitochondrial genes.

Factorial invariance of the Wechsler Intelligence Scale for Children, Fifth Edition, across the UK, US and Australia & New Zealand.

OBJECTIVES: This study examined the factorial invariance of the factor structure of the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) across the UK, US and Australia & New Zealand (A&NZ). The factorial equivalence of cognitive assessments should be demonstrated before assuming cross-culture generalizability and interpretations of score comparisons. METHODS: Data were obtained from the UK, US and A&NZ normative standardizations of the WISC-V. The samples consisted of 415 UK, 2200 US and 528 A&NZ children, aged 6-16. Confirmatory factor analysis was applied separately in each sample to establish the baseline model. Next, tests of factorial invariance were undertaken using the recommended hierarchical approach, firstly across the UK and A&NZ samples and then across the UK and US samples. RESULTS: The five-factor first-order scoring model was found to be excellent fit across all three samples independently. Strict factorial invariance of the WISC-V was demonstrated firstly across the UK and A&NZ and secondly the UK and US nationally representative standardization samples. Comparison of latent means found small but significant differences in female children across the UK and A&NZ samples. CONCLUSIONS: Consistent with previous research, these results demonstrate the generality of the WISC-V factor structure across the UK, US and A&NZ. Furthermore, as the WISC-V factor structure aligns with the Cattell-Horn-Carroll (CHC) model of cognitive abilities, the results add further support to the cross-cultural generalizability of the CHC model. Small but significant differences in latent factor scores found across samples support the development and use of local normative data.

The role of attention in the emergence of the evaluative and incidental self-reference effects.

The self-reference effect (SRE) is a memory advantage produced by encoding information in a self-relevant manner. The "evaluative" SRE arises when people engage in explicit self-evaluation/reflection to process to-be-remembered items, while the "incidental" SRE occurs when self-referential information (e.g., one's own name) is co-presented with to-be-remembered items but is irrelevant to a given task. Using a divided-attention paradigm, the present study examined potential differences in the attentional requirements of the evaluative and incidental SREs. During encoding, personality-trait words were presented simultaneously with the participant's own or a celebrity's name. The participants' task was either to evaluate whether each word described themselves/the celebrity (evaluative encoding) or to indicate the location of each word (incidental encoding), in the presence or absence of a secondary task. A subsequent recognition test with a remember/know procedure showed better overall recognition and enhanced episodic recollection for words presented with one's own name vs. another name, with this SRE being larger in the evaluative than incidental encoding condition. Critically, divided attention at encoding attenuated the magnitudes of both evaluative and incidental SREs to a comparable degree in overall recognition and episodic recollection. These findings suggest that both the evaluative and incidental SREs are resource-demanding, effortful mnemonic benefits.

Initial combination therapy with macitentan and tadalafil in patients with pulmonary arterial hypertension, with and without cardiac comorbidities.

AIMS: According to current guidelines, initial monotherapy should be considered for pulmonary arterial hypertension (PAH) patients with cardiopulmonary comorbidities. This analysis of combined data from the TRITON and REPAIR clinical trials, assesses efficacy and safety of initial double combination therapy in patients without vs. with 1-2 cardiac comorbidities. METHODS AND RESULTS: Data were combined for patients from TRITON (NCT02558231) and REPAIR (NCT02310672) on initial macitentan and tadalafil double combination therapy (overall set, n = 148) and two subgroups defined as patients without cardiac comorbidities (n = 62) and those with 1-2 cardiac comorbidities (n = 78). Patients with ≥3 comorbidities were excluded from these studies. For the overall set, the median (Q1-Q3) duration of combined macitentan and tadalafil exposure was 513.0 (364.0-778.0) days, and was similar between subgroups. Change from baseline to Week 26 for pulmonary vascular resistance was -55% and -50% for patients without and with 1-2 cardiac comorbidities, respectively; marked improvements in other hemodynamic and functional parameters were also observed, although functional parameters improved to a lesser extent in patients with comorbidities. At Week 26, the majority of patients had improved PAH risk status, according to the non-invasive four-strata and REVEAL Lite 2.0 methods. The safety profile of initial macitentan plus tadalafil combination therapy was consistent with the known profiles of the two drugs, and similar between the subgroups. CONCLUSIONS: Initial double combination therapy with macitentan plus tadalafil is efficacious in patients with PAH with 1-2 cardiac comorbidities and those without, with similar safety and tolerability profiles between the two groups.

Impact of pre-transplant immune checkpoint inhibitor use on post-transplant outcomes in HCC: A systematic review and individual patient data meta-analysis.

BACKGROUND AND AIM: Treatment with immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) prior to liver transplantation (LT) has been reported; however, ICIs may elevate the risk of allograft rejection and impact other clinical outcomes. This study aims to summarize the impact of ICI use on post-LT outcomes. MATERIALS AND METHODS: In this individual patient data meta-analysis, we searched databases to identify HCC cases treated with ICIs before LT, detailing allograft rejection, HCC recurrence, and overall survival. We performed Cox regression analysis to identify risk factors for allograft rejection. RESULTS: Among 91 eligible patients, with a median (interquartile range [IQR]) follow-up of 690.0 (654.5) days, there were 24 (26.4%) allograft rejections, 9 (9.9%) HCC recurrences, and 9 (9.9%) deaths. Age (adjusted hazard ratio [aHR] per 10 years=0.72, 95% confidence interval [CI]=0.53, 0.99, P=0.044) and ICI washout time (aHR per 1 week=0.92, 95% CI=0.86, 0.99, P=0.022) were associated with allograft rejection. The median (IQR) washout period for patients with ≤20% probability of allograft rejection was 94 (196) days. Overall survival did not differ between cases with and without allograft rejection (log-rank test, p=0.2). Individuals with HCC recurrence had fewer median (IQR) ICI cycles than those without recurrence (4.0 [1.8]) vs. 8.0 [9.0]); p=0.025). The proportion of patients within Milan post-ICI was lower for those with recurrence vs. without (16.7% vs. 65.3%, p=0.032) CONCLUSION: Patients have acceptable post-LT outcomes after ICI therapy. Age and ICI washout length relate to the allograft rejection risk, and a 3-month washout may reduce it to that of patients without ICI exposure. Number of ICI cycles and tumor burden may affect recurrence risk. Large prospective studies are necessary to confirm these associations. IMPACT AND IMPLICATIONS: This systematic review and individual patient data meta-analysis of 91 patients with hepatocellular carcinoma and immune checkpoint inhibitors use prior to liver transplantation suggests acceptable overall post-transplant outcomes. Older age and longer immune checkpoint inhibitor washout period have a significant inverse association with the risk of allograft rejection. A 3-month washout may reduce it to that of patients without ICI exposure. Additionally, a higher number of immune checkpoint inhibitor cycles and tumor burden within Milan criteria at the completion of immunotherapy may predict a decreased risk of hepatocellular carcinoma recurrence, but this observation requires further validation in larger prospective studies. CODE FOR INTERNATIONAL PROSPECTIVE REGISTER OF SYSTEMATIC REVIEWS (PROSPERO): CRD42023494951.

Addressing corneal opacity after herpes zoster infection.

A 15-year-old boy was referred for corneal opacity evaluation. The patient had a previous herpes zoster virus (HZV) infection-varicella-zoster virus (VZV)-with ocular manifestation 1 year ago. After the infection, he developed a central corneal scar and decreased corrected distance visual acuity (CDVA) in the right eye. The slitlamp examination showed the right eye with central corneal opacity (involving anterior stroma), lacuna area between the haze, fluorescein negative, and no vascularization near the scar (Figure 1JOURNAL/jcrs/04.03/02158034-202406000-00019/figure1/v/2024-07-10T174224Z/r/image-tiff). The patient had been treated with oral valacyclovir and topical corticosteroids without any improvement of visual acuity or changes in opacity within the 1-year follow-up. His CDVA was 20/200 (-4.50 -0.75 × 25) in the right eye and counting fingers (-4.00) in the left eye. Intraocular pressure was 12 mm Hg in both eyes. Fundoscopy was normal in the right eye, but he had a macular scar in the left eye (diagnosed when he was 7 years). The left eye had no cornea signs. The patient has no comorbidity or previous surgeries. Considering this case, a corneal central scar in a 15-year-old boy, legally single eye only, and assuming it is an opacity in the anterior stroma, would you consider surgery for this patient? If so, which would you choose: Would you consider an excimer laser treatment of his ametropia while partially removing his opacity, a phototherapeutic keratectomy (PTK), or a PTK followed by a topography-guided treatment, femtosecond laser-assisted anterior lamellar keratoplasty (FALK), or deep anterior lamellar keratoplasty (DALK) or penetrating keratoplasty (depending on the scar depth)? Would you consider prophylactic acyclovir during and after surgery? Would you consider any other surgical step to prevent delayed corneal healing-persistent epithelial defect? Before the surgical approach, would you consider treating this patient with topical losartan (a transforming growth factor [TGF]-ß signaling inhibitor)? Would you first perform the surgery (which one) and then start the medication? Furthermore, if so, how long would you treat this patient? Would you consider treatment with another medication?

Effective low-cost pediatric vision screening by naive nonophthalmic examiners using the 'Arclight' device.

PURPOSE: To explore whether a low-cost ophthalmoscope (Arclight) can be used by naive nonophthalmic examiners to effectively screen for pediatric eye disease. METHODS: Fifty-four children (108 eyes) were examined by five medical students using an Arclight. Gold standard examination was performed by an ophthalmologist using a slit lamp and indirect ophthalmoscope. Examinations performed included ophthalmoscopy of the optic disc, estimation of the cup-to-disc ratio (CDR), corneal light reflex test (CRT), Bruckner's reflex test (BRT), and evaluation of refractive error. We determined the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the nonophthalmologist's Arclight exam compared to the gold standard findings of comprehensive evaluation by pediatric ophthalmologists. RESULTS: Using the Arclight, the optic nerve exam was successfully completed in 65% of patients. CDRs above and below 0.5 could be determined with 66.7% sensitivity and 84.4% specificity. Arclight CRT measurements were significant (P < .00001) predictors of strabismus, with 80% sensitivity, 95.1%, specificity, 80% PPV, and 95.1% NPV. BRT was not a significant predictor of amblyopia, with a 34.6% sensitivity, 85.7% specificity, 69.2% PPV, and 58.5% NPV. Refractive error was estimated with a success rate of 81% for emmetropia, 38% for myopia, and 21% for hyperopia. The Arclight ease-of-use was rated on average as 4.4 (SD = 0.9) on a scale of 1 to 5, with 1 being the hardest and 5 being the easiest. CONCLUSIONS: Our study shows the Arclight as an affordable and effective alternative to the traditional ophthalmoscope for assessing eye disease in children. This device can improve eye health services in under-resourced regions.

Investigating the Effect of Enterally Administered Capromorelin on Body Weight in Mice (Mus musculus).

Significant weight loss in mice (Mus musculus) is a welfare concern and can alter physiology and behavior in ways that may confound research aims. In this study, factorial design was used to investigate the effect of enterally administered capromorelin on changes in mouse body weight overall and with various research-related interventions, such as administration of analgesics, anesthesia, or surgery. BALB/c mice (n = 61 [27 males/34 females] for analysis) were randomized into 8 intervention-treatment groups with 2 treatment allocations: capromorelin (10 mg/kg) or control, and 4 intervention allocations: no intervention; buprenorphine extended-release (XR) alone; buprenorphine XR, meloxicam, and anesthesia; or surgery under anesthesia with buprenorphine XR, meloxicam, and bupivacaine administered. Mice were habituated to handling, weighing, and voluntary consumption of condensed milk, which was used as the control solution and later a vehicle for capromorelin delivery, for 5 d (days 0 to 4). Then, mice received their interventions followed by 3 days of daily treatment or control administration (days 7 to 9). Body weights were measured daily (days 8 to 11 and day 14) to compare with baseline weights (days 0 to 4 and day 7) and evaluate for treatment and intervention effects on body weight. The interventions resulted in a decrease in group body weights 3 and 4 d after the interventions were conducted. Overall, body weights increased more in mice given capromorelin compared with control, and mice treated with capromorelin returned to, or exceeded, baseline weights faster. The weight loss was mitigated by capromorelin administration in all interventions except for the buprenorphine XR-only group. It is recommended to clinically consider enterally administered capromorelin to mitigate research-induced weight loss in mice.

The utility of software-detected non-invasive tear break-up in comparison to fluorescein tear break-up measurements.

Purpose: The purpose of this study is to characterize and discuss the difference between software-detected non-invasive tear break-up time (NIBUT) and the traditional clinical method of fluorescein break-up time (FBUT). Methods: Tear interferometry with the KOWA DR-1α (Kowa, Japan) and a standardized comprehensive ocular surface/tear evaluation were performed in 307 eyes. Software-detected NIBUT in the KOWA DR-1α images and the investigator-detected FBUT were compared. Results: Software-detected NIBUT was significantly shorter than investigator-measured FBUT. NIBUT was 3.1 ± 2.5 s (mean ± SD), whereas FBUT was 4.8 ± 3.0 s. This difference was due to three different patterns or conditions: a spot break immediately after eyelid opening, moderate to severe keratitis sicca, and epithelial basement membrane corneal dystrophy (EBMD). In these cases, rapid tear film disruption was not captured by FBUT. A spot break immediately after eye opening that rapidly disappears was observed with conjunctivochalasis. This type of break-up may be difficult to detect using fluorescein because the human eye cannot catch such rapid blinks or post-blink events. In the second group with severe corneal epithelial disease, break-up may occur over the entire corneal surface upon eye opening, and distinct fluorescein tear break-up may not be identified because of poor dye dilution or spread over the corneal surface, whereas the non-invasive break-up is not solution-dependent, and the software can detect a distinct appearance. In the third group with EBMD, it is possible that focal break-up in the fluorescein pattern over the epithelial elevations, which might be missed visually, can be detected by software in video images. Conclusion: We found that software-detected NIBUT is more sensitive in detecting tear break-up, can identify certain tear film disruptions that are missed by traditional FBUT, and may be more useful in distinguishing certain tear disorders.

Exposure to blue light reduces antimicrobial resistant Pseudomonas aeruginosa isolated from dog ear infections.

Introduction: Pseudomonas aeruginosa is a leading cause of canine otitis externa. Enrofloxacin is often applied topically to treat this condition, although recalcitrant and recurring infections are common. There is evidence that exposure to blue light (400-470 nm) has a bactericidal effect on P. aeruginosa and other microorganisms. Methods: In the present study, we tested the biocidal effect of blue light (375-450 nm), alone or in combination with enrofloxacin, against six isolates of P. aeruginosa from dogs with otitis externa (5 of which were resistant to enrofloxacin). Results: Treatment of planktonic cell cultures with blue light resulted in significant (p < 0.5) reductions in Colony Forming Units (CFU) for all seven strains tested, in some cases below the limit of detection. The greatest bactericidal effect was observed following exposure to light at 405 nm wavelength (p < 0.05). Exposure to blue light for 20 min usually resulted in a greater reduction in Pseudomonas aeruginosa than enrofloxacin treatment, and combination treatment typically resulted in the largest reductions in CFU. Analysis of the genome sequences of these strains established that enrofloxacin resistance was likely the result of a S466F substitution in GyrB. However, there was no clear association between genotype and susceptibility to blue light treatment. Discussion: These results suggest that blue light treatment, particularly at 405 nm wavelength, and especially in combination with enrofloxacin therapy, could be an effective treatment for otherwise recalcitrant canine otitis externa caused by Pseudomonas aeruginosa. It may also provide a way of extending the usefulness of enrofloxacin therapy which would otherwise be ineffective as a sole therapeutic agent.

Pragmatic Emergency Department Intervention Reducing Default Quantity of Opioid Tablets Prescribed.

Introduction: The opioid epidemic is a major cause of morbidity and mortality in the United States. Prior work has shown that emergency department (ED) opioid prescribing can increase the incidence of opioid use disorder in a dose-dependent manner, and systemic changes that decrease default quantity of discharge opioid tablets in the electronic health record (EHR) can impact prescribing practices. However, ED leadership may be interested in the impact of communication around the intervention as well as whether the intervention may differentially impact different types of clinicians (physicians, physician assistants [PA], and nurse practitioners). We implemented and evaluated a quality improvement intervention of an announced decrease in EHR default quantities of commonly prescribed opioids at a large, academic, urban, tertiary-care ED. Methods: We gathered EHR data on all ED discharges with opioid prescriptions from January 1, 2019-December 6, 2021, including chief complaint, clinician, and opioid prescription details. Data was captured and analyzed on a monthly basis throughout this time period. On March 29, 2021, we implemented an announced decrease in EHR default dispense quantities from 20 tablets to 12 tablets for commonly prescribed opioids. We measured pre- and post-intervention quantities of opioid tablets prescribed per discharge receiving opioids, distribution by patient demographics, and inter-clinician variability in prescribing behavior. Results: The EHR change was associated with a 14% decrease in quantity of opioid tablets per discharge receiving opioids, from 14 to 12 tablets (P = <.001). We found no statistically significant disparities in prescriptions based on self-reported patient race (P = 0.68) or gender (P = 0.65). Nurse practitioners and PAs prescribed more opioids per encounter than physicians on average and had a statistically significant decrease in opioid prescriptions associated with the EHR change. Physicians had a lesser but still significant drop in opioid prescribing in the post-intervention period. Conclusion: Decreasing EHR defaults is a robust, simple tool for decreasing opioid prescriptions, with potential for implementation in the 42% of EDs nationwide that have defaults exceeding the recommended 12-tablet supply. Considering significant inter-clinician variability, future interventions to decrease opioid prescriptions should examine the effects of combining EHR default changes with targeted interventions for clinician groups or individual clinicians.

Identification and Characterization of Critical Processing Parameters in the Fabrication of Double-Emulsion Poly(lactic-co-glycolic) Acid Microparticles.

In the past several decades, polymeric microparticles (MPs) have emerged as viable solutions to address the limitations of standard pharmaceuticals and their corresponding delivery methods. While there are many preclinical studies that utilize polymeric MPs as a delivery vehicle, there are limited FDA-approved products. One potential barrier to the clinical translation of these technologies is a lack of understanding with regard to the manufacturing process, hindering batch scale-up. To address this knowledge gap, we sought to first identify critical processing parameters in the manufacturing process of blank (no therapeutic drug) and protein-loaded double-emulsion poly(lactic-co-glycolic) acid MPs through a quality by design approach. We then utilized the design of experiments as a tool to systematically investigate the impact of these parameters on critical quality attributes (e.g., size, surface morphology, release kinetics, inner occlusion size, etc.) of blank and protein-loaded MPs. Our results elucidate that some of the most significant CPPs impacting many CQAs of double-emulsion MPs are those within the primary or single-emulsion process (e.g., inner aqueous phase volume, solvent volume, etc.) and their interactions. Furthermore, our results indicate that microparticle internal structure (e.g., inner occlusion size, interconnectivity, etc.) can heavily influence protein release kinetics from double-emulsion MPs, suggesting it is a crucial CQA to understand. Altogether, this study identifies several important considerations in the manufacturing and characterization of double-emulsion MPs, potentially enhancing their translation.