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Retinal nonperfusion (RNP) is an important biomarker for diabetic retinopathy (DR). Data suggest that consistent anti-VEGF pharmacotherapy can slow RNP development. The RECOVERY trial evaluated the impact of aflibercept (Eylea, Regeneron) on RNP among eyes with proliferative DR (PDR).Prospective, randomized clinical trial with treatment crossover in the second year.Eyes with PDR and RNP.At baseline, the subjects were randomized 1:1 to monthly (arm 1) or quarterly (arm 2) intravitreal 2 mg aflibercept. At the beginning of year 2, the treatment arms were crossed over so that the monthly-dosed subjects subsequently received quarterly dosing and the quarterly-dosed subjects subsequently received monthly dosing.Change in total RNP area (mmAmong all subjects, from baseline to year 2, the mean RNP increased from 235 mmThrough year 2 of the RECOVERY trial, both treatment arms experienced significant increases in RNP. Despite the expansion of the RNP area in nearly all subjects, 82% of subjects demonstrated an improvement in DRSS levels from baseline, with no subjects experiencing worsening in DRSS scores.

BTK inhibitor exposure increases significantly when coadministered with CYP3A inhibitors, which may lead to dose-related toxicities. This study explored the pharmacokinetics, efficacy, and safety of zanubrutinib when coadministered with moderate or strong CYP3A inhibitors in 26 patients with relapsed or refractory B-cell malignancies. Coadministration of zanubrutinib (80 mg BID) with moderate CYP3A inhibitors fluconazole and diltiazem or zanubrutinib (80 mg QD) with strong CYP3A inhibitor voriconazole resulted in comparable exposures to zanubrutinib (320 mg QD) with AUC

Introduction: Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B-cell lymphomas. Zanubrutinib was designed to achieve improved therapeutic concentrations and minimize off-target activities putatively accounting, in part, for the adverse effects seen with other BTK inhibitors.Areas covered: This drug profile covers zanubrutinib clinical pharmacology and the translation of pharmacokinetics (PK) and pharmacodynamics (PD) to clinical efficacy and safety profiles, by highlighting key differences between zanubrutinib and other BTK inhibitors. We discuss PK, sustained BTK occupancy, and potential factors affecting PK of zanubrutinib, including food effects, hepatic impairment, and drug-drug interactions. These data, along with exposure-response analyses, were used to support the recommended dose of 320 mg, either once daily or as 160 mg twice daily. Translation of PK/PD attributes into clinical effects was demonstrated in a randomized, phase 3 head-to-head study comparing it with ibrutinib in patients with Waldenstrom macroglobulinemia.Expert opinion: Among the approved BTK inhibitors, zanubrutinib is less prone to PK modulation by intrinsic and extrinsic factors, leading to more consistent, sustained therapeutic exposures and improved dosing convenience. Zanubrutinib PK/PD has translated into durable responses and improved safety, representing an important new treatment option for patients who benefit from BTK therapy.

This report summarizes a totality-of-evidence approach supporting recommendation of a 320-mg total daily dose, either as 160-mg twice daily (BID) or 320-mg once daily (QD) for zanubrutinib in patients with mantle cell lymphoma. Data were derived from a phase 2 study in patients receiving 160-mg BID and a phase 1/2 study with similar response rates observed with 160-mg BID or 320-mg QD. Given the limited number of patients in the QD dose group, population pharmacokinetics and exposure-response analyses were employed to bridge the two regimens. The analyses showed that similar plasma exposure and BTK inhibition were achieved, and differences in trough concentration and maximum plasma concentration between the two regimens are unlikely to have a meaningful impact on efficacy and safety endpoints. The totality of data, including pharmacokinetic, pharmacodynamic, safety, efficacy, and exposure-response analyses, provided support for the recommended 320-mg total daily dose for the approved indication.

Purpose: The purpose of this study is to provide updated national estimates on the annual number, educational environments, and secondary school outcomes of students who are D/deaf and hard of hearing (D/HH) receiving special education (SpEd) and related services in the United States. Method: We performed a retrospective cross-sectional descriptive analysis of Individuals with Disabilities Education Act, Part B, Section 618 data from 2012 to 2018. Participants included students 6–21 years old in SpEd with “hearing impairment” reported as their primary disability. The general population of students in secondary school served as a comparator, via Current Population Survey data. We described the annual number of students (a) overall, (b) by educational environment, and (c) by reason for exiting SpEd, including the proportion graduating from and dropping out of secondary school. We described variation over time. Results: The median annual number of students was 67,655, with minimal variation by year. The proportion in general education (GenEd) for ≥ 80% of the day increased by 4.2% over 6 years from 57.8% to 62.0%, whereas the proportions in GenEd for < 40% and 40%–79% of the day decreased by 1.6% and 1.3%, respectively. Proportions in the remainder of the environments changed < 1.0% each. Of exiters, 86.8% of students graduated, whereas 3.9% dropped out, compared to a dropout rate of 5.0% in the general population. Conclusion: From 2012 to 2018, students who are D/HH receiving SpEd in the United States have spent increasingly more time in GenEd, most graduated from high school, and few dropped out, with dropout patterns appearing similar to the general population.

Intraoperative computed tomography scanning with O-arm and use of Stealth navigation can improve surgical outcomes in a variety of orthopedic subspecialties. In spine surgery, the accuracy, precision, and safety of pedicle screw and interbody implant placement has improved. This technology is now routinely used in percutaneous pedicle screw placement and minimally invasive sacroiliac joint fusion. Other applications include, but are not limited to, isthmic pars defect repair, lumbosacral pseudoarticulation resection in Bertolotti's syndrome, radiofrequency ablation, and en bloc tumor resection. Intraoperative navigation has numerous applications, and use of this technology should continue to evolve as the technology advances. [ Orthopedics . 2023;46(2):e89–e97.]

Objective: The Deaf community is an ethnolinguistic minority group. Low sensitivity to Deaf culture contributes to health disparities among Deaf patients. This study determines the level of sensitivity to Deaf culture among otolaryngology-head and neck surgery (OHNS) and audiology trainees. Methods: Cross-sectional survey study of OHNS and audiology trainees from 10 large US institutions. Trainees were queried on their exposure to and comfort with Deaf patients and their education on, attitude toward, and awareness and knowledge of Deaf culture. Sensitivity to Deaf culture was operationalized as awareness and knowledge of Deaf culture. These were assessed using a 35-item instrument that was previously developed using a d/Deaf community-based participatory approach to research. We used T-tests to compare the sample to previous samples of medical students with training in Deaf culture (MS-TDCs) and general practitioners (GPs). Results: There were 91 completed surveys (response rate 44.5%). Almost all were aware of Deaf culture (97.8%). The mean knowledge score was 55.0% (standard deviation (SD) 13.4%), which was significantly higher than that for GPs at 43.0% (SD 15.0%) (95% confidence interval 8.1%, 15.8%, P Conclusion: This sample of OHNS and audiology trainees was more sensitive to Deaf culture than GPs but less sensitive than MS-TDCs. Developing specialty-specific education may be warranted. Level of evidence: 4.

Zanubrutinib is a potent, second‐generation Bruton’s tyrosine kinase inhibitor that is currently being investigated in patients with B‐cell malignancies and recently received accelerated approval in the United States for treatment of relapsed/refractory mantle cell lymphoma. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the PKs of zanubrutinib and identify the potential impact of intrinsic and extrinsic covariates on zanubrutinib PK. Data across nine clinical studies of patients with B‐cell malignancies and data of healthy volunteers (HVs) were included in this analysis, at total daily doses ranging from 20 to 320 mg. In total, 4,925 zanubrutinib plasma samples from 632 subjects were analyzed using nonlinear mixed‐effects modeling. Zanubrutinib PKs were adequately described by a two‐compartment model with sequential zero‐order then first‐order absorption, and first‐order elimination. A time‐dependent residual error model was implemented in order to better capture the observed maximum concentration variability in subjects. Baseline alanine aminotransferase and health status (HVs or patients with B‐cell malignancies) were identified as statistically significant covariates on the PKs of zanubrutinib. These factors are unlikely to be clinically meaningful based on a sensitivity analysis. No statistically significant differences in the PKs of zanubrutinib were observed based on age, sex, race (Asian, white, and other), body weight, mild or moderate renal impairment (creatinine clearance ≥ 30 mL/minute as estimated by Cockcroft‐Gault), baseline aspartate aminotransferase, bilirubin, tumor type, or use of acid‐reducing agents (including proton pump inhibitors). These results support that no dose adjustment is considered necessary based on the aforementioned factors.

This review provides an overview of current applications of deep learning methods within breast radiology. The diagnostic capabilities of deep learning in breast radiology continue to improve, giving rise to the prospect that these methods may be integrated not only into detection and classification of breast lesions, but also into areas such as risk estimation and prediction of tumor responses to therapy. Remaining challenges include limited availability of high-quality data with expert annotations and ground truth determinations, the need for further validation of initial results, and unresolved medicolegal considerations. KEY POINTS: • Deep learning (DL) continues to push the boundaries of what can be accomplished by artificial intelligence (AI) in breast imaging with distinct advantages over conventional computer-aided detection. • DL-based AI has the potential to augment the capabilities of breast radiologists by improving diagnostic accuracy, increasing efficiency, and supporting clinical decision-making through prediction of prognosis and therapeutic response. • Remaining challenges to DL implementation include a paucity of prospective data on DL utilization and yet unresolved medicolegal questions regarding increasing AI utilization.

Aim This study aims to assess the potential effects of zanubrutinib on the activity of cytochrome P450 (CYP) enzymes and drug transporter proteins using a cocktail probe approach. Methods Patients received single oral doses of probe drugs alone and after at least 8 days of treatment with zanubrutinib 160 mg twice daily in a single-sequence study in 18 healthy male volunteers. Simultaneous doses of 10 mg warfarin (CYP2C9) and 2 mg midazolam (CYP3A) were administered on Day 1 and Day 14, 0.25 mg digoxin (P-glycoprotein [P-gp]) and 10 mg rosuvastatin (breast cancer resistance protein [BCRP]) on Day 3 and Day 16, and 20 mg omeprazole (CYP2C19) on Day 5 and Day 18. Pharmacokinetic (PK) parameters were estimated from samples obtained up to 12 h post dose for zanubrutinib; 24 h for digoxin, omeprazole and midazolam; 48 h for rosuvastatin; and 144 h for warfarin. Results The ratios (%) of geometric least squares means (90% confidence intervals) for the area under the concentration-time curve from time zero to the last quantifiable concentration in the presence/absence of zanubrutinib were 99.80% (97.41-102.2%) for S-warfarin; 52.52% (48.49-56.88%) for midazolam; 111.3% (103.8-119.3%) for digoxin; 89.45% (78.73-101.6%) for rosuvastatin; and 63.52% (57.40-70.30%) for omeprazole. Similar effects were observed for maximum plasma concentrations. Conclusions Zanubrutinib 320 mg total daily dose had minimal or no effect on the activity of CYP2C9, BCRP and P-gp, but decreased the systemic exposure of CYP3A and CYP2C19 substrates (mean reduction

Hemoglobin functions as a tetrameric oxygen transport protein, with each subunit containing a heme cofactor. Its denaturation, either in vivo or in vitro, involves autoxidation to methemoglobin, followed by cofactor loss and globin unfolding. We have proposed a global disassembly scheme for human methemoglobin, linking hemin (ferric protoporphyrin IX) disassociation and apoprotein unfolding pathways. The model is based on the evaluation of circular dichroism and visible absorbance measurements of guanidine-hydrochloride-induced disassembly of methemoglobin and previous measurements of apohemoglobin unfolding. The populations of holointermediates and equilibrium disassembly parameters were estimated quantitatively for adult and fetal hemoglobins. The key stages are characterized by hexacoordinated hemichrome intermediates, which are important for preventing hemin disassociation from partially unfolded, molten globular species during early disassembly and late-stage assembly events. Both unfolding experiments and independent small angle x-ray scattering measurements demonstrate that heme disassociation leads to the loss of tetrameric structural integrity. Our model predicts that after autoxidation, dimeric and monomeric hemichrome intermediates occur along the disassembly pathway inside red cells, where the hemoglobin concentration is very high. This prediction suggests why misassembled hemoglobins often get trapped as hemichromes that accumulate into insoluble Heinz bodies in the red cells of patients with unstable hemoglobinopathies. These Heinz bodies become deposited on the cell membranes and can lead to hemolysis. Alternatively, when acellular hemoglobin is diluted into blood plasma after red cell lysis, the disassembly pathway appears to be dominated by early hemin disassociation events, which leads to the generation of higher fractions of unfolded apo subunits and free hemin, which are known to damage the integrity of blood vessel walls. Thus, our model provides explanations of the pathophysiology of hemoglobinopathies and other disease states associated with unstable globins and red cell lysis and also insights into the factors governing hemoglobin assembly during erythropoiesis.

Sarcopenia has been observed to be a predictor of mortality in international studies of patients with metastatic disease of the spine. This study aimed to validate sarcopenia as a prognostic tool in a New Zealand setting. A secondary aim of this study was to assess the intra-observer reliability of measurements of psoas and vertebral body cross sectional areas on computed tomography imaging.A cohort of patients who had presented to Waikato Hospital with secondary neoplasia in the spinal column from 2014 to 2018 was selected. Cross sectional psoas and vertebral body areas were measured at the mid-pedicle L3 level, followed by calculation of the psoas to vertebral body cross sectional area ratio. Psoas to vertebral body cross sectional area ratio was compared with survivorship. The strength of the correlation between sarcopenia and survivorship was compared with the correlation between serum albumin and survivorship, as well as the correlation between the Metastatic Spine Risk Index (MSRI) and survivorship.A total of 110 patients who received operative (34) and non-operative (76) were included. The results demonstrate that psoas to vertebral body cross sectional area ratio is not statistically significantly correlated with survivorship (p=0.53). Serum albumin is significantly correlated with survivorship (pThis study failed to demonstrate the utility for the psoas to vertebral body cross sectional area ratio that other studies have demonstrated in estimating survivorship. Serum albumin levels remain a useful prognostic indicator in patients with secondary tumours in the vertebral column.

Zanubrutinib is a highly selective, potent, orally available, targeted covalent inhibitor (TCI) of Bruton's tyrosine kinase (BTK). This work investigated the in vitro drug metabolism and transport of zanubrutinib, and its potential for clinical drug–drug interactions (DDIs). Phenotyping studies indicated cytochrome P450 (CYP) 3A are the major CYP isoform responsible for zanubrutinib metabolism, which was confirmed by a clinical DDI study with itraconazole and rifampin. Zanubrutinib showed mild reversible inhibition with half maximal inhibitory concentration (IC50) of 4.03, 5.69, and 7.80 μM for CYP2C8, CYP2C9, and CYP2C19, respectively. Data in human hepatocytes disclosed induction potential for CYP3A4, CYP2B6, and CYP2C enzymes. Transport assays demonstrated that zanubrutinib is not a substrate of human breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP)1B1/1B3, organic cation transporter (OCT)2, or organic anion transporter (OAT)1/3 but is a potential substrate of the efflux transporter P‐glycoprotein (P‐gp). Additionally, zanubrutinib is neither an inhibitor of P‐gp at concentrations up to 10.0 μM nor an inhibitor of BCRP, OATP1B1, OATP1B3, OAT1, and OAT3 at concentrations up to 5.0 μM. The in vitro results with CYPs and transporters were correlated with the available clinical DDIs using basic models and mechanistic static models. Zanubrutinib is not likely to be involved in transporter‐mediated DDIs. CYP3A inhibitors and inducers may impact systemic exposure of zanubrutinib. Dose adjustments may be warranted depending on the potency of CYP3A modulators., This study evaluates the in vitro metabolism and drug–drug interaction (DDI) potential of zanubrutinib through interaction with CYP450s and transporters. CYP450 phenotyping using recombinant CYP enzymes and other studies identified CYP3A as the major enzyme responsible for the metabolism of zanubrutinib, which leads to its major DDIs when co‐administered with CYP3A modulators.

Molybdenum bis(imido) bis(thiolato) complexes of the type Mo(NtBu)2(SR)2 (R = tBu (1), iPr (2)) were synthesized and evaluated as precursors for the aerosol-assisted chemical vapor deposition (AACV...

Abscisic acid (ABA) is a plant hormone that regulates tolerance to abiotic stress. In this study, we evaluated the effect of exogenous different concentrations of ABA (0, 0.5, 1, 10, 100 and 200 μM) to mitigate oxidative stress in Platycladus orientalis (L.) Franco exposed to 100 mM hydrogen peroxide (H2O2), and its effects on reactive oxygen metabolism. Results indicated that exposure to 100 mM H2O2 significantly increased the contents of H2O2, malondialdehyde (MDA), ascorbic acid, total glutathione, and proline, and the activities of superoxide dismutase (SOD) and catalase (CAT) in P. orientalis leaves, while peroxidase (POD) activity decreased. The transcript levels of Cu/Zn-SOD, CAT, GR, APX, MDAR, and GST were upregulated in P. orientalis after 48 h of H2O2-induced stress. Compared with 100 and 200 μM ABA, lower ABA concentrations (0.5, 1, and 10 μM) significantly enhanced the activities of SOD, POD and CAT, and increased the contents of ascorbic acid, total glutathione, and proline in H2O2-treated seedlings at 48 h, accompanied by reduced H2O2 and MDA contents. Among the three lower concentrations of ABA, the 1 μM ABA concentration had the strongest effect on enzyme activities and the contents of antioxidant compounds. Among all the ABA concentrations, 1 μM ABA had the strongest effect to increase the transcript levels of Cu/Zn-SOD, CAT, GR, APX and MDAR in P. orientalis under H2O2-induced stress. This study revealed that an appropriate concentration of ABA effectively mitigated the damage caused by reactive oxygen species to P. orientalis via regulating the antioxidant defense system.

Epithelial adherens junctions (AJs) and tight junctions (TJs) undergo disassembly and reassembly during morphogenesis and pathological states. The membrane–cytoskeleton interface plays a crucial role in junctional reorganization. Protein 4.1R (4.1R), expressed as a diverse array of spliceoforms, has been implicated in linking the AJ and TJ complex to the cytoskeleton. However, which specific 4.1 isoform(s) participate and the mechanisms involved in junctional stability or remodeling remain unclear. We now describe a role for epithelial-specific isoforms containing exon 17b and excluding exon 16 4.1R (4.1R(+17b)) in AJs. 4.1R(+17b) is exclusively co-localized with the AJs. 4.1R(+17b) binds to the armadillo repeats 1–2 of β-catenin via its membrane-binding domain. This complex is linked to the actin cytoskeleton via a bispecific interaction with an exon 17b–encoded peptide. Exon 17b peptides also promote fodrin–actin complex formation. Expression of 4.1R(+17b) forms does not disrupt the junctional cytoskeleton and AJs during the steady-state or calcium-dependent AJ reassembly. Overexpression of 4.1R(−17b) forms, which displace the endogenous 4.1R(+17b) forms at the AJs, as well as depletion of the 4.1R(+17b) forms both decrease junctional actin and attenuate the recruitment of spectrin to the AJs and also reduce E-cadherin during the initial junctional formation of the AJ reassembly process. Expressing 4.1R(+17b) forms in depleted cells rescues junctional localization of actin, spectrin, and E-cadherin assembly at the AJs. Together, our results identify a critical role for 4.1R(+17b) forms in AJ assembly and offer additional insights into the spectrin–actin–4.1R-based membrane skeleton as an emerging regulator of epithelial integrity and remodeling.

Purpose Evaluate the impact of intravitreal aflibercept (Eylea, Regeneron, Tarrytown, NY) on retinal non-perfusion (RNP) in eyes with proliferative diabetic retinopathy (PDR). Design Prospective, randomized clinical trial. Subjects Eyes with treatment-naive PDR and extensive RNP without diabetic macular edema. Methods Patients were randomized 1:1 to intravitreal 2-mg aflibercept every-4-weeks (Monthly) or every-12-weeks (Quarterly). Main Outcome Measures The primary outcome measure was change in total RNP area (mm2) from baseline to year 1. Secondary outcomes included ischemic index (ISI), neovascularization area, diabetic retinopathy severity scale (DRSS) scores, visual acuity, central retinal thickness, visual function questionnaire score, and adverse events. Mean and 95% confidence interval (CI) were calculated for each outcome. Results Through 1-year, the Monthly (n=20) & Quarterly (n=20) cohorts received 11.0 & 3.95 mean aflibercept injections, & DRSS scores improved ≥2 steps in 74% & 67% of patients, respectively. Among all patients through 1-year, mean total area of RNP increased from 235 mm2 (CI, 183-288) to 266 mm2 (CI, 299-303; P=0.18) and ISI increased from 25.8% (CI, 20.9-30.7) to 31.9% (CI, 27.6-36.3; P=0.004). RNP outcomes favored monthly-dosing. Mean total RNP increased from 207 mm2 (CI, 143-270) at baseline to 268 mm2 (CI, 212-324; P=0.01) at 1-year in the Quarterly cohort, and remained stable at 264 mm2 at baseline (CI, 176-351) and 1-year (CI, 209-318; P=0.70) in the Monthly cohort (P=0.05, Monthly vs. Quarterly cohorts), with a difference of 56.8 mm2 in total RNP (CI: -47.8-161; P=0.28) at baseline and -4.19 mm2 (CI: -79.4-71.0; P=0.91) at 1-year between the Monthly and Quarterly cohorts. While many eyes demonstrated increased areas of RNP longitudinally (24, 66.7%), this was more common with Quarterly dosing (14, 77.8%), and a proportion of eyes (12, 33.3%) demonstrated localized areas of apparent reperfusion of non-perfused retina, more commonly in the Monthly cohort (8, 44.4%). Conclusions Widespread evidence of retinal reperfusion with aflibercept-dosing of PDR eyes with extensive RNP was not identified, and therefore the primary outcome of RECOVERY was not met; nevertheless, zones of apparent reperfusion were detected in some patients and a dose-response was identified with a reduction of RNP progression with monthly compared to quarterly dosing.

Tungsten(VI) oxo complexes of the type WO(OR)3L [R = C(CH3)2CF3, C(CF3)2CH3, CH(CF3)2, L = hexafluoroacetylacetonate (hfac), ethyl trifluoroacetoacetonate (etfac), acetylacetonate (acac)] bearing partially fluorinated alkoxide and/or chelating ligands were synthesized. Thermal decomposition behavior and mass spectrometry (MS) fragmentation patterns of selected examples were studied. The thermolysis products of WO(OC(CF3)2CH3)3(hfac) were characterized by nuclear magnetic resonance and gas chromatography–MS. Studies of the sublimation behavior of the complexes demonstrated that their volatility depends on the degree of fluorination. Comparative studies of the deposition of tungsten oxide by chemical vapor deposition (CVD) and aerosol-assisted CVD were carried out using WO(OC(CF3)2CH3)3(hfac) as a single-source precursor. WOx materials were successfully deposited by both deposition methods, but the deposits differed in morphology, structure, and crystallinity.

In knowledge discovery studies, association rules mining has been extensively studied to discover hidden knowledge and relationships among set of items in a transactional dataset. Most research on association rule mining focuses on discovering frequent patterns based on the most frequent items occurring in the dataset. However, the process of extracting rare rules has received less attention. In medical dataset studies, the discovery of rare association rules (RARs) is more challenging, because it could likely be used to obtain more potentially rare and unusual knowledge for physicians, beside frequent association rules. Hence, the aim of this paper is to discover non-frequent or rare-unusual association rules (RUARs) from a stroke medical dataset to provide potential meaningful knowledge to the user domain. A discretization method needs to be performed as the data preprocessing step before generating rules. To the best of our knowledge, fewer studies have focused on the role of discretization results to support the extraction of a better amount and quality of RUARs, particularly for medical datasets. In addition, the extracted RUARs is expected to provide potential new unusual insights on stroke risk patterns. This paper applies mutual information measure to discretize a stroke examination dataset collected from a medical center in Taiwan. The interval merging method was proposed to simplify the discrete form and enrich the quality of generated rules. Towards the end, rare association rules, with relatively low support, were generated by employing the Apriori-Rare method accordingly. In addition, a filtering process was applied to the content of the rule itemsets to discover the expected set of RUARs for physicians. Furthermore, the extracted RUARs was analyzed based on the relative risk values toward the occurrence of stroke. Results indicated that the mutual information discretization outperformed the traditional discretization methods in terms of how the discretization scheme can support the extraction of RUARs with a better quantity and quality measurements for further analysis purpose in medical point of view. Moreover, the proposed method had a relatively higher number of RUARs. The knowledge of unusual rule patterns from rare association rules might provide potential new and unusual insights for medical pratitioners and increase the awareness of stroke examination results.

Introduction: Our goal was to standardize intraoperative analgesic regimens for pediatric ambulatory tonsillectomy by eliminating local anesthetic use and to determine its impact on postoperative pain measures, while controlling for other factors. Methods: We assembled a quality improvement team at an ambulatory surgery center. They introduced a standardized anesthetic protocol, involving American Society of Anesthesiologists Classification 1 and 2 patients undergoing adenotonsillectomy. Local anesthesia elimination was the project’s single intervention. We collected pre-intervention data (79 cases) from July 5 to September 17, 2019 and post-intervention data (59 cases) from September 25 to December 17, 2019. The intervention requested that surgeons eliminate the use of local anesthetics. The following outcomes measures were evaluated using statistical process control charts and Shewhart’s theory of variation: (1) maximum pain score in the post-anesthesia care unit, (2) total post-anesthesia care unit minutes, and (3) postoperative opioid rescue rate. Results: No special cause variation signal was detected in any of the measures following the intervention. Conclusions: Our data suggest that eliminating intraoperative local anesthetic use does not worsen postoperative pain control at our facility. The intervention eliminated the added expenses and possible risks associated with local anesthetic use. This series is unique in its standardization of anesthetic regimen in a high-volume ambulatory surgery center with the exception of local anesthesia practices. The study results may impact the standardized clinical protocol for pediatric ambulatory adenotonsillectomy at our institution and may hold relevance for other centers.

Introduction This study aimed to assess the impact of the COVID-19 pandemic on the sleep of adult patients of a multidisciplinary sleep clinic. Methods Patients were invited to complete online surveys: Survey 1 in October 2020 (increased COVID-19 restrictions) followed by Survey 2 in February 2021 (after easing of restrictions for a COVIDSafe summer). Results Of the 746 patients invited to participate, 73 completed and 8 partially returned Survey 1 (mean age 50.1 years, range 21–83 years, 58% female). Subsequently, 46 completed and 5 partially answered Survey 2. In Survey 1, 22/74 (29.7%) reported reduced sleep quantity and 31/75 (41.3%) indicated worse sleep quality compared with prior to the pandemic. In Survey 2, 33/46 (71.7%) described unchanged sleep quantity whilst 5/46 (10.9%) reported increased sleep quantity since easing COVID-19 restrictions. 36/46 (78.3%) indicated unchanged sleep quality whereas 5/46 (10.9%) described improved sleep quality since easing restrictions. However, 9/46 (19.6%) reported that their sleep remained worse compared with pre-pandemic. For patients who completed both surveys, there was no significant change in Insomnia Severity Index scores (Survey 1 mean 13.6, Survey 2 mean 12.9, mean difference -0.67 [95%CI -2.02, 0.68], p=0.32) or PROMIS Sleep-Related Impairment 8a T-scores (Survey 1 mean 59.0, Survey 2 mean 59.5, mean difference 0.44 [95%CI -1.55, 2.42], p=0.66). Discussion The COVID-19 pandemic has negatively affected the sleep of 44% of patients. Following easing of restrictions, symptoms of insomnia and sleep-related impairment did not change significantly, and 19.6% reported that their sleep was not back to their pre-pandemic baseline.

Relación entre los serotipos y las secuencias génicas de hemaglutinina de

To assess the effectiveness of an active learning approach to measuring the contrast sensitivity function (CSF) in patients with various degrees of dry age-related macular degeneration (AMD) under multiple luminance conditions.Cross-sectional study.Patients with AMD (26 intermediate AMD, 19 AMD with subretinal drusenoid deposits [SDD], 20 geographic atrophy [GA]) and 23 age-matched controls were tested with the Manifold Contrast Vision Meter (Adaptive Sensory Technology) and the qCSF algorithm, which applies active learning to estimate a model of the CSF's global shape. Testing was performed under conditions of standard and low luminance. For each AMD severity, the area under log CSF (AULCSF) and contrast sensitivities at individual spatial frequencies were calculated for analysis. Low-luminance deficits (LLDs) for visual acuity (VA) and AULCSF were calculated as the difference between standard and low luminance values.Progressive decreases in AULCSF were observed as disease severity increased. For standard luminance, pairwise comparisons revealed significant differences between control/intermediate AMD (P.0005), control/SDD (P.0005), control/GA (P.0005), and intermediate AMD/GA (P.005). Similarly, for low luminance, pairwise comparisons revealed significant differences between the controls and each disease group (all P.0005), in addition to significant differences between intermediate AMD/SDD (P.005), and intermediate AMD/GA (P.005). No correlations were found between LLD VA and LLD AULCSF in any AMD groups.Contrast sensitivity measured via qCSF under both standard- and low-luminance conditions correlates with advancing stages of dry AMD. The interaction between luminance and contrast sensitivity appears to reflect a different aspect of visual function than the interaction between luminance and VA.

This review provides an overview of current applications of deep learning methods within breast radiology. The diagnostic capabilities of deep learning in breast radiology continue to improve, giving rise to the prospect that these methods may be integrated not only into detection and classification of breast lesions, but also into areas such as risk estimation and prediction of tumor responses to therapy. Remaining challenges include limited availability of high-quality data with expert annotations and ground truth determinations, the need for further validation of initial results, and unresolved medicolegal considerations. KEY POINTS: • Deep learning (DL) continues to push the boundaries of what can be accomplished by artificial intelligence (AI) in breast imaging with distinct advantages over conventional computer-aided detection. • DL-based AI has the potential to augment the capabilities of breast radiologists by improving diagnostic accuracy, increasing efficiency, and supporting clinical decision-making through prediction of prognosis and therapeutic response. • Remaining challenges to DL implementation include a paucity of prospective data on DL utilization and yet unresolved medicolegal questions regarding increasing AI utilization.

Cochlear implant depth of insertion affects audiologic outcomes and can be measured in adults using plain films obtained in the "cochlear view." The objective of this study was to assess interrater and intrarater reliability of measuring depth of insertion using cochlear view radiography.Prospective, observational.Tertiary referral pediatric hospital.Patients aged 11 months to 20 years (median, 4 years; interquartile range [IQR], 1-8 years) undergoing cochlear implantation at our institution were studied over 1 year. Children underwent cochlear view imaging on postoperative day 1. Films were deidentified and 1 image per ear was selected. Two cochlear implant surgeons and 2 radiologists evaluated each image and determined angular depth of insertion. Images were re-reviewed 6 weeks later by all raters. Inter- and intrarater reliability were calculated with intraclass correlation coefficients (ICCs).Fifty-seven ears were imaged from 42 children. Forty-nine ears (86%) had successful cochlear view x-rays. Median angular depth of insertion was 381° (minimum, 272°; maximum, 450°; IQR, 360°-395°) during the first round of measurement. Measurements of the same images reviewed 6 weeks later showed median depth of insertion of 382° (minimum, 272°; maximum, 449°; IQR, 360°-397°). Interrater and intrarater reliability ICCs ranged between 0.81 and 0.96, indicating excellent reliability.Postoperative cochlear view radiography is a reliable tool for measurement of cochlear implant depth of insertion in infants and children. Further studies are needed to determine reliability of intraoperatively obtained cochlear view radiographs in this population.

COVID-19 is a rapidly growing global pandemic caused by a novel coronavirus. With no vaccine or definitive treatment, public health authorities have recommended a strategy of "social distancing," reducing individual interaction, canceling elective procedures, and limiting nonessential services. Health care providers must determine what procedures are considered "elective," balancing risk of treatment delays with that of coronavirus exposure to patient, family, and providers. Given critical periods for language development and the long-term impact of auditory deprivation, some audiologic and otologic services should be considered essential. In this article, we describe the experience of a quaternary referral pediatric hospital in Seattle, the epicenter of COVID-19 in the United States, and share strategies for risk minimization employed by Seattle Children's Hospital. We hope that this work can be a reference for other centers continuing care for children who are deaf and hard of hearing during the COVID-19 and future resource-limiting crises.

Coronavirus disease 2019 (COVID-19) is a novel coronavirus resulting in high mortality in the adult population but low mortality in the pediatric population. The role children and adolescents play in COVID-19 transmission is unclear, and it is possible that healthy pediatric patients serve as a reservoir for the virus. This article serves as a summary of a single pediatric institution's response to COVID-19 with the goal of protecting both patients and health care providers while providing ongoing care to critically ill patients who require urgent interventions. A significant limitation of this commentary is that it reflects a single institution's joint effort at a moment in time but does not take into consideration future circumstances that could change practice patterns. We still hope dissemination of our overall response at this moment, approximately 8 weeks after our region's first adult case, may benefit other pediatric institutions preparing for COVID-19.

This thorough QT (TQT) study evaluated the effect of zanubrutinib on electrocardiogram (ECG) parameters by using concentration‐QTc (C‐QTc) analysis as the primary analysis for this study. Part A of the study determined the safety and tolerability of a single supratherapeutic dose of zanubrutinib (480 mg) in healthy volunteers. Part B was a randomized, blinded, placebo‐controlled and positive‐controlled, four‐way crossover, TQT study of single therapeutic (160 mg) and supratherapeutic (480 mg) doses of zanubrutinib, placebo, and open‐label moxifloxacin 400 mg. Thirty‐two participants received at least 1 dose of zanubrutinib, and 26 participants completed all 4 periods. Zanubrutinib did not have any effect on heart rate or cardiac conduction (pulse rate, QRS interval, or T‐wave morphology) and was generally well‐tolerated. Using C‐QTc analysis, the predicted placebo‐corrected change‐from‐baseline QT interval using Fridericia’s formula (ΔΔQTcF) was −3.4 msec (90% confidence interval: −4.9 to −1.9 msec) at peak concentrations of the 480 mg dose. A QT effect (ΔΔQTcF) exceeding 10 msec could be excluded within the observed concentration range at 160 and 480 mg doses. Assay sensitivity was established by moxifloxacin with 90% lower bound exceeding 5 msec. Implementing a C‐QTc analysis prospectively in this TQT study resulted in a substantially smaller sample size to maintain a similar study power as shown in the traditional time‐point analysis. A single 160‐mg or 480‐mg zanubrutinib dose did not prolong the QTc interval or have any other clinically relevant effects on ECG parameters.

BACKGROUND AND OBJECTIVE: To investigate predictors of visual outcomes in patients who underwent vitrectomy for full-thickness macular hole (FTMH) with at least 1 year of follow-up. PATIENTS AND METHODS: Retrospective, noncomparative, consecutive case series of 132 eyes of 122 patients who underwent surgical repair of idiopathic FTMH with at least 1 year of follow-up. Predictors of visual acuity (VA) outcomes were analyzed using linear regression. RESULTS: Mean follow-up time was 22.2 months. Twenty-three eyes (17.4%) had age-related macular degeneration (AMD), of which 17 (73.9%) cases were mild and nonexudative. At final follow-up, poor preoperative VA ( P < .001), perioperative complications ( P < .001), AMD ( P < .001), and delay from preoperative evaluation to surgery ( P = .037) were significant predictors of final VA. In multiple regression, these variables remained significant ( P < .001, P = .011, P < .001, and P = .002, respectively). CONCLUSION: Poor preoperative VA, perioperative complications, AMD, and delay to surgery were significant predictors of final VA following FTMH repair. [ Ophthalmic Surg Lasers Imaging Retina . 2018;49:566–570.]

Aims Diabetic retinopathy (DR) and diabetic macular edema (DME) can be evaluated using telemedicine systems, such as the Intelligent Retinal Imaging Systems (IRIS), in patients with Diabetes Mellitus (DM). In an endocrinology-based population utilizing IRIS we determine prevalence rates of DR and DME, and identify associated epidemiologic correlations. Methods This is a multicenter, retrospective chart review using screening data from IRIS. Centers for Disease Control and Prevention (CDC) data on epidemiologic variables (by county) namely, prevalence of DM, incidence of DM, obesity, and time of physical inactivity, were compared against prevalence rates of DR found at screening. Results A total of 10,223 eyes of 5,242 patients with DM were imaged. DR and DME were noted in 1781 (33.98%) and 226 imaging studies (4.31%) respectively. The coefficient of determination was greatest for incidence of DM (R2 = 0.92), followed by DM prevalence (R2 = 0.79), obesity, (R2 = 0.67), and physical inactivity (R2 = 0.34). The presence of DR during screening varied significantly by county (p Conclusions Screening in counties with a higher incidence of DM led to a higher prevalence of identified DR at time of screening. The current work suggests that telemedicine screening in areas known to have a higher incidence of DM may be worthwhile.

The doping effects of C and Sn on the magnetic properties, structure, and microstructure of melt spun YCo5-xMx (M = C and Sn; x = 0–0.3) ribbons are studied. The permanent magnetic properties of Br = 5.7 kG, iHc = 1.8 kOe, and (BH)max = 2.1 MGOe are obtained for the binary YCo5 ribbon, and they are largely increased to Br = 5.6–5.7 kG, iHc = 7.0–14.7 kOe, (BH)max = 5.3–6.5 MGOe for C-doping ribbons and Br = 5.5–5.6 kG, iHc = 5.2–14.4 kOe, (BH)max = 3.8–6.2 MGOe for Sn-doping ribbons, respectively. All studied ribbons mainly consist of hexagonal 1:5 phase with space group of P6/mmm. The entrance of C or Sn into the crystal structure of 1:5 phase modifies lattice constants and increases Curie temperature. The microstructure is effectively refined from 100 to 300 nm for binary ribbons to 10–50 nm for C-doping and 60–100 nm for Sn-doping ribbons, respectively. For high Sn-content YCo4.7Sn0.3 ribbon, Y5Sn3 precipitates with 10–20 nm in diameter form in the matrix, and these nonmagnetic phase may act as a pinning site to impede magnetization reversal and thus contribute to enhance coercivity. Magnetic property enhancement with C-doping is attributed to the formation of Y(Co, C)5 phase and microstructure refinement, while one with Sn-doping is related to the formation of Y(Co, Sn)5 phase, microstructure refinement, and the induction of nonmagnetic Y5Sn3 precipitates.

Purpose To evaluate the effect of targeted retinal photocoagulation (TRP) on visual and anatomic outcomes and treatment burden in eyes with diabetic macular edema (DME). Design Phase I/II prospective, randomized, controlled clinical trial. Participants Forty eyes of 29 patients with center-involved macular edema secondary to diabetes mellitus. Methods Eyes with center-involved DME and Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) between 20/32 and 20/320 (Snellen equivalent) were randomized 1:1 to monotherapy with 0.3 mg ranibizumab (Lucentis, Genentech, South San Francisco, CA) or combination therapy with 0.3 mg ranibizumab and TRP guided by widefield fluorescein angiography. All eyes received 4 monthly ranibizumab injections followed by monthly examinations and pro re nata (PRN) re-treatment through 36 months. Targeted retinal photocoagulation was administered outside the macula to areas of retinal capillary nonperfusion plus a 1–disc area margin in the combination therapy arm at week 1, with re-treatment at months 6, 18, and 25, if indicated. Main Outcome Measures Mean change in ETDRS BCVA from baseline and number of intravitreal injections administered. Results At baseline, mean age was 55 years, mean BCVA was 20/63 (Snellen equivalent), and mean central retinal subfield thickness (CRT) was 530 μm. Thirty-four eyes (85%) completed month 36, at which point mean BCVA improved 13.9 and 8.2 letters ( P = 0.20) and mean CRT improved 302 and 152 μm ( P = 0.03) in the monotherapy and combination therapy arms, respectively. The mean number of injections administered through month 36 was 24.4 (range, 10–34) and 27.1 (range, 12–36), with 73% (362/496) and 80% (433/538) of PRN injections administered ( P = 0.004) in the monotherapy and combination therapy arms, respectively. Goldmann visual field isopter III-4e area decreased by 2% and 18% in the monotherapy and combination therapy arms, respectively ( P = 0.30). Conclusions In this 3-year randomized trial of 40 eyes with DME, there was no evidence that combination therapy with ranibizumab and TRP improved visual outcomes or reduced treatment burden compared with ranibizumab alone.

Chicken infectious anaemia (CIA) is a disease with a highly economic impact in the poultry industry. The infected chickens are characterized by aplastic anaemia and extreme immunosuppression, followed by the increased susceptibility to secondary infectious pathogens and suboptimal immune responses for vaccination. Commercially available CIA vaccines are routinely used in the breeders in Taiwan to protect their progeny with maternal-derived antibodies. However, CIA cases still occur in the field and little is known about the genetic characteristics of Taiwanese chicken anaemia viruses (CAVs). In this study, CAV DNA was detected in 72 of 137 flocks collected during 2010-2015. Among the PCR-positive samples, the coding regions of 51 CAVs were sequenced. Phylogenetic analysis of the VP1 gene revealed that, although most of Taiwanese CAVs belonged to genotypes II and III, some isolates were clustered into a novel genotype (genotype IV). Moreover, a Taiwanese isolate in this novel genotype IV appeared to be derived from a recombination event between genotypes II and III viruses. Five Taiwanese CAV isolates were highly similar to the vaccine strains, 26P4 or Del-Ros. Taken together, these results indicate that the sequences of CAVs in Taiwan are variable, and inter-genotypic recombination had occurred between viruses of different genotypes. Moreover, vaccine-like strains might induce clinical signs of CIA in chickens. Our findings could be useful for understanding the evolution of CAVs and development of a better control strategy for CIA.