Lower FIB-4 threshold in patients with diabetes improves diagnostic accuracy of the test in a Hispanic population.

Background: Non-invasive tests (NITs) can be used to estimate the severity of fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) but their diagnostic accuracy is variable. Hispanic patients are at increased risk of NAFLD and diabetes. We evaluate the diagnostic performance of the fibrosis index based on 4 factors (FIB-4) in a population of Hispanic patients who underwent vibration-controlled transient elastography (VCTE). Methods: A total of 1,524 patients underwent VCTE at University of California, Los Angeles from July 18, 2019 to June 7, 2022. Ultimately 110 patients were identified as Hispanic, with confirmed NAFLD. Sensitivity, specificity, positive predictive value and negative predictive value of FIB-4 threshold ≥1.3 were calculated. Logistic regression models were used to determine updated thresholds for patients with and without diabetes based on Youden's index. Results: Of the 110 patients, the majority (65%) were female. Prevalence of diabetes was higher in the group with clinically significant fibrosis (76% vs. 36%, P<0.001). Using a FIB-4 threshold ≥1.3 to predict clinically significant fibrosis (F2-F4 on VCTE), area under the receiver operating characteristic (AUROC) was 0.74. By incorporating diabetes status, AUROC was 0.81 when employing a FIB-4 threshold of ≥1.0 in patients with diabetes and ≥1.5 in patients without diabetes. Conclusions: Using a FIB-4 threshold of ≥1.0 in patients with diabetes and ≥1.5 in patients without diabetes improves the diagnostic performance of the test. The new FIB-4 including diabetes status will lead to improved screening in patients who are at risk of clinically significant fibrosis.

Nontraditional Treatment of Hepatic Encephalopathy.

The pathophysiology of hepatic encephalopathy (HE) is complex, with hyperammonemia playing a central role in its development. Traditional therapies for HE have targeted ammonia and include medications such as lactulose and rifaximin. Although these agents are considered standard of care, nontraditional treatments seek to affect other factors in the pathogenesis of HE. Finally, procedural therapies include albumin dialysis, shunt closure, and the ultimate cure for HE, which is liver transplant. The treatments discussed provide alternative options for patients who have failed standard of care. However, more high-quality studies are needed to routinely recommend many of these agents.

The relationship between severe hypertensive diseases of pregnancy and moderate-severe bronchopulmonary dysplasia.

OBJECTIVE: Determine the association between severe hypertensive disease of pregnancy (HDP) with moderate-severe bronchopulmonary dysplasia (BPD) in preterm infants (< 31 weeks' gestation). STUDY DESIGN: Preterm birth cohort study of 693 mother-infant dyads. Severe HDP was defined as severe preeclampsia, HELLP syndrome or eclampsia. The outcome was moderate-severe BPD classified at 36 weeks corrected gestational age, per the NICHD Consensus statement. RESULTS: 225 (32%) mothers developed severe HDP and 234 (34%) infants had moderate-severe BPD. There was an interaction between severe HDP and gestational age (p = 0.03). Infants born at < 25 weeks gestation to mothers with HDP had increased odds for moderate-severe BPD compared to infants of normotensive mothers delivering at the same gestational age. Infants born > 28 weeks to mothers with severe HDP had decreased odds for the outcome, though not statistically significant. CONCLUSIONS: Severe HDP has a differential effect on the development of moderate-severe BPD based on gestational age.

The Relationship Between Severe Hypertensive Diseases of Pregnancy and Moderate-Severe Bronchopulmonary Dysplasia.

Objective: Determine the association between severe hypertensive disease of pregnancy (HDP) with moderate-severe bronchopulmonary dysplasia (BPD) in preterm infants (< 31 weeks' gestation). Study Design: Preterm birth cohort study of 693 mother-infant dyads. Severe HDPwas defined as severe preeclampsia, HELLP syndrome or eclampsia. The outcome was moderate-severe BPD classified at 36 weeks corrected gestational age, based on the NICHD Consensusstatement. Results: 225 (32%) mothers developed severe HDP and 234 (34%) infants hadmoderate-severe BPD. There was an interaction between severe HDP and gestational age (p=0.03). Infants born at earlier gestational ages to mothers with HDP had increased odds for moderate-severe BPD compared to infants of normotensive mothers delivering at the same gestational age. Infants born at later gestational ages to mothers with severe HDP had decreased odds for the outcome. Conclusions: Severe HDP has a differential effect on the development of moderate-severe BPD based on gestational age.

Customer Archetypes in Hearing Health Care.

PURPOSE: The purpose of this study is to determine if there are unique customer archetypes that can describe the motivations behind consumer buying choice (in person or online) for hearing aids in hearing health care. METHOD: A consumer survey was developed from themes that arose during 11 semistructured interviews with adults who had no previous hearing aid experience. Using Qualtrics research panels, a 28-item questionnaire was distributed online to U.S. residents above the age of 50 years with no previous hearing aid experience. A quota of 1,000 completed responses was set, with a maximum of 70% of respondents identifying as White. Completed surveys were obtained from 1,377 individuals. Three hundred forty responses were excluded due to ineligibility and/or poor response quality. RESULTS: Two unique customer archetypes were developed using five factors identified in the data set: Physician Trust, Sociability, Comfort Buying Online, Verify Sources, and Reliance on Others. Eighty-four percent of respondents chose an in-person pathway for hearing health care. There was no association between customer archetype and pathway selection choice. CONCLUSIONS: The two archetypes reflect those with greater comfort with consuming health care online and in person, respectively. However, both archetypes are likely to use in-person models of hearing health care at the present time. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24431212.

Seroprevalence of leptospirosis among blood donors in an endemic area.

Thailand is known to be endemic for leptospirosis. This bacterium may pose a potential risk to transfusion safety. This study was a cross-sectional study examining the seroprevalence of leptospirosis among Thai blood donors. A total of 1053 serum specimens collected from blood donors residing in 5 regions of Thailand during March to September 2020 were included in this study. All samples were tested for the presence of antibodies to 22 leptospiral serovars using the microscopic agglutination test (MAT) and anti-Leptospira IgG antibodies using commercially available enzyme immunoassay. We found no evidence of recent exposure to Leptospira spp. in sera of healthy Thai blood donors by MAT, including those in higher-risk areas. However, in this same group, we did find small numbers of past exposure (1.7%) to Leptospira spp. by IgG ELISA. According to the findings of this study, there is currently no evidence for implementing new blood banking procedures to identify possible carriers in Thailand, however these should be continually monitored and revised according to the infectious disease burden in each country. It should be noted that there was a difference in the occupation rate between the general population reported in Thailand and blood donors in this study; it may not reflect the actual situation in the country.

Two RNA-binding proteins mediate the sorting of miR223 from mitochondria into exosomes.

Fusion of multivesicular bodies (MVBs) with the plasma membrane results in the secretion of intraluminal vesicles (ILVs), or exosomes. The sorting of one exosomal cargo RNA, miR223, is facilitated by the RNA-binding protein, YBX1 (Shurtleff et al., 2016). We found that miR223 specifically binds a 'cold shock' domain (CSD) of YBX1 through a 5' proximal sequence motif UCAGU that may represent a binding site or structural feature required for sorting. Prior to sorting into exosomes, most of the cytoplasmic miR223 resides in mitochondria. An RNA-binding protein localized to the mitochondrial matrix, YBAP1, appears to serve as a negative regulator of miR223 enrichment into exosomes. miR223 levels decreased in the mitochondria and increased in exosomes after loss of YBAP1. We observed YBX1 shuttle between mitochondria and endosomes in live cells. YBX1 also partitions into P body granules in the cytoplasm (Liu et al., 2021). We propose a model in which miR223 and likely other miRNAs are stored in mitochondria and are then mobilized by YBX1 to cytoplasmic phase condensate granules for capture into invaginations in the endosome that give rise to exosomes.

Preserving the Role of the Audiologist in a Clinical Technology, Consumer Channel, Clinical Service Model of Hearing Healthcare.

The past decade has been characterized by significant changes in the distribution and sale of hearing aids. Alternatives to the clinical technology, clinical channel, clinical service (i.e., traditional) hearing healthcare delivery model have been driven by growth in hearing aid dispensaries housed in large retail establishments and direct-to-consumer hearing aid sales by internet-based companies unaffiliated with major hearing aid manufacturers (e.g., Eargo). These developments have been accompanied by acceleration in the growth of teleaudiology services as a direct result of the COVID-19 pandemic. The resulting development of nontraditional hearing aid distribution and sales models can be categorized into distinct archetypes as reviewed earlier in this publication. This article will review the Clinical Technology-Consumer Channel-Clinical Service model as exemplified by Jabra Enhance. We will describe a completely digital model of hearing aid distribution and sales that maintains the professional service component throughout the client journey to include an online tone test, the use of a risk mitigation questionnaire, virtual consultations, remote hearing aid adjustments, and the establishment and monitoring of client-centered treatment goals. Furthermore, this article will review the Jabra Enhance model within the context of consumer healthcare decision-making theory with a focus on the Consumer Decision-Making Model.

The Evolution of Redo Liver Transplantation Over 35 Years: Analysis of 654 Consecutive Adult Liver Retransplants at a Single Center.

OBJECTIVE: To examine liver retransplantation (ReLT) over 35 years at a single center. BACKGROUND: Despite the durability of liver transplantation (LT), graft failure affects up to 40% of LT recipients. METHODS: All adult ReLTs from 1984 to 2021 were analyzed. Comparisons were made between ReLTs in the pre versus post-model for end-stage liver disease (MELD) eras and between ReLTs and primary-LTs in the modern era. Multivariate analysis was used for prognostic modeling. RESULTS: Six hundred fifty-four ReLTs were performed in 590 recipients. There were 372 pre-MELD ReLTs and 282 post-MELD ReLTs. Of the ReLT recipients, 89% had one previous LT, whereas 11% had ≥2. Primary nonfunction was the most common indication in the pre-MELD era (33%) versus recurrent disease (24%) in the post-MELD era. Post-MELD ReLT recipients were older (53 vs 48, P = 0.001), had higher MELD scores (35 vs 31, P = 0.01), and had more comorbidities. However, post-MELD ReLT patients had superior 1, 5, and 10-year survival compared with pre-MELD ReLT (75%, 60%, and 43% vs 53%, 43%, and 35%, respectively, P < 0.001) and lower in-hospital mortality and rejection rates. Notably, in the post-MELD era, the MELD score did not affect survival. We identified the following risk factors for early mortality (≤12 months after ReLT): coronary artery disease, obesity, ventilatory support, older recipient age, and longer pre-ReLT hospital stay. CONCLUSIONS: This represents the largest single-center ReLT report to date. Despite the increased acuity and complexity of ReLT patients, post-MELD era outcomes have improved. With careful patient selection, these results support the efficacy and survival benefit of ReLT in an acuity-based allocation environment.

Enzymatic reactions of AGO4 in RNA-directed DNA methylation: siRNA duplex loading, passenger strand elimination, target RNA slicing, and sliced target retention.

RNA-directed DNA methylation in plants is guided by 24-nt siRNAs generated in parallel with 23-nt RNAs of unknown function. We show that 23-nt RNAs function as passenger strands during 24-nt siRNA incorporation into AGO4. The 23-nt RNAs are then sliced into 11- and 12-nt fragments, with 12-nt fragments remaining associated with AGO4. Slicing recapitulated with recombinant AGO4 and synthetic RNAs reveals that siRNAs of 21-24 nt, with any 5'-terminal nucleotide, can guide slicing, with sliced RNAs then retained by AGO4. In vivo, RdDM target locus RNAs that copurify with AGO4 also display a sequence signature of slicing. Comparing plants expressing slicing-competent versus slicing-defective AGO4 shows that slicing elevates cytosine methylation levels at virtually all RdDM loci. We propose that siRNA passenger strand elimination and AGO4 tethering to sliced target RNAs are distinct modes by which AGO4 slicing enhances RNA-directed DNA methylation.

Interventions for infantile esotropia.

BACKGROUND: Infantile esotropia (IE) is the inward deviation of the eye. Various aspects of the clinical management of IE are unclear; mainly, the most effective type of intervention and the age at intervention. OBJECTIVES: To examine the effectiveness and optimal timing of surgical and non-surgical treatment options for IE to improve ocular alignment and achieve or allow the development of binocular single vision. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, one other database, and three trials registers (November 2021). We did not use any date or language restrictions in the electronic searches for trials.  SELECTION CRITERIA: We included randomized trials and quasi-randomized trials comparing any surgical or non-surgical intervention for IE. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology and graded the certainty of the body of evidence for six outcomes using the GRADE classification. MAIN RESULTS: We included two studies with 234 children with IE. The first study enrolled 110 children (mean age 26.9 ± 14.5 months) with an onset of esotropia before six months of age, and large-angle IE defined as esotropia of ≥ 40 prism diopters. It was conducted between 2015 and 2018 in a tertiary care hospital in South Africa. It compared a maximum of three botulinum toxin injections with surgical intervention of bimedial rectus muscle recession, and children were followed for six months. There were limitations in study design and implementation; the risk of bias was high, or we had some concerns for most domains.  Surgery may increase the incidence of treatment success, defined as orthophoria or residual esotropia of ≤ 10 prism diopters, compared with botulinum toxin injections, but the evidence was very uncertain (risk ratio (RR) of treatment success 1.88, 95% confidence interval (CI) 1.27 to 2.77; 1 study, 101 participants; very low-certainty evidence). The results should be read with caution because 23 children with > 60 prism diopters at baseline in the surgery arm also received botulinum toxin at the time of surgery to augment the recessions. There was no evidence of an important difference between surgery and botulinum toxin injections for over-correction (> 10 prism diopters) of deviation (RR 0.29, 95% CI 0.06 to 1.37; 1 study, 101 participants; very low-certainty evidence), or additional interventions required (RR 0.66, 95% CI 0.36 to 1.19; 1 study, 101 participants; very low-certainty evidence). No major complications of surgery were observed in the surgery arm, while children experienced various complications in the botulinum toxin arm, including partial transient ptosis in 9 (16.7%) children, transient vertical deviation in 3 (5.6%) children, and consecutive exotropia in 13 (24.1%) children. No other outcome data for our prespecified outcomes were reported.  The second study enrolled 124 children with onset of esotropia before one year of age in 12 university hospitals in Germany and the Netherlands. It compared bilateral recession with unilateral recession surgeries, and followed children for three months postoperatively. Very low-certainty evidence suggested that there was no evidence of an important difference between bilateral and unilateral surgeries in the presence of binocular vision (numbers with event unclear, P = 0.35), and over-correction (RR of having exotropia 1.09, 95% CI 0.45 to 2.63; 1 study, 118 participants). Dissociated vertical deviation, latent nystagmus, or both were observed in 8% to 21% of participants. AUTHORS' CONCLUSIONS: Medial rectus recessions may increase the incidence of treatment success compared with botulinum toxin injections alone, but the evidence was very uncertain. No evidence of important difference was found between bilateral surgery and unilateral surgery.  Due to insufficient evidence, it was not possible to resolve the controversies regarding type of surgery, non-surgical intervention, or age of intervention in this review. There is clearly a need to conduct good quality trials in these areas to improve the evidence base for the management of IE.

Assessment of Consumer Attitudes Following Recent Changes in the US Hearing Health Care Market.

Importance: The addition of over-the-counter hearing aid (HA) options has transformed the way individuals can access hearing health care (HHC). However, although critical to their adoption and use, consumer attitudes and opinions about direct-to-consumer (DTC) models of health care are often understudied. Objective: To assess how recent DTC market changes in HHC delivery may be associated with consumer choice and attitudes towards specific HHC models. Design, Setting, and Participants: A mixed-methods survey, distributed online between March 22 and 25, 2022, using Qualtrics Survey Panels. Participants were US residents older than 50 years with no previous hearing aid experience, enrolled using consecutive sampling. A minimum of 1000 completed responses was set; once the 70% threshold was met, any future respondent who identified as White would not be given the survey. Main Outcomes and Measures: Respondents were asked to report their level of comfort with using different variations of DTC-HHC and asked about their previous experience with other DTC health care models. Respondents then reported which model (in-person vs online) of HHC they would most likely pursue. Results: Of 1377 respondents, 1037 were included in the survey study (mean [SD] age, 61.4 [7.84] years; 714 [69.0%] were female; 674 [65.0%] were White). Most respondents reported discomfort with pursuing hearing aids via DTC pathways, with 84% (874 of 1037) indicating they would pursue HHC via an in-person model. Individuals who were older (odds ratio [OR], 0.95; 95% CI, 0.92-0.98), reported an income greater than $150 000 (OR, 0.29; 95% CI, 0.08-0.91), and were not interested in HA (OR, 0.42; 95% CI, 0.23-0.79) were less likely to pursue HHC online. Those who had previous experience with DTC health care (OR, 1.97; 95% CI, 1.27-3.02), and did not have (OR, 2.61; 95% CI, 1.59-4.31) or were uncertain (OR, 2.05; 95% CI, 1.13-3.70) about their insurance coverage for HA were more likely to pursue HHC online. Conclusions and Relevance: Current consumer attitudes and opinions found in this survey study suggest that DTC-HHC may not find immediate acceptance by most potential HA seekers in the US.

Healthcare-associated hepatitis B and C transmission to patients in the EU/EEA and UK: a systematic review of reported outbreaks between 2006 and 2021.

Healthcare-associated transmission was the second most common hepatitis B (HBV) and hepatitis C (HCV) transmission route according to 2006-2012 European surveillance data, but data quality and completeness issues hinder comprehensive characterisation of this important issue. We carried out a systematic review of published literature on healthcare-associated transmission of HBV or HCV in European Union (EU) and European Economic Area (EEA) countries and the United Kingdom to complement surveillance data and identify higher-risk settings. We searched the PubMed and Embase databases and grey literature over the period January 2006 to September 2021, for publications reporting transmission events after 2000 in the EU/EEA and UK related to a healthcare setting or procedure. We collected data on the country, number of patients, setting type and route of transmission. In 65 publications from 16 countries, 43 HBV and 48 HCV events were identified resulting in 442 newly infected patients. Most events were reported from Italy (7 HBV and 12 HCV), Germany (8 HBV and 5 HCV) and the United Kingdom (8 HBV and 5 HCV). The number of patients infected from a single source within an event ranged from 1 to 53. Five large outbreaks of over 20 cases were identified, including two in Poland and one each in Belgium, Hungary and Slovakia. The majority of transmission events occurred through blood transfusions or in dialysis units. However, there were a number of outbreaks in seemingly low risk settings such as CT/MRI scanning units. A failure to adequately follow infection prevention control (IPC) precautions was reported in 30% of included studies. Healthcare-associated transmission of hepatitis B and C continues to occur in a range of community and hospital settings across EU/EEA countries and often results in large outbreaks, although the true extent of the situation cannot be fully determined due to under-reporting. Strict IPC precautions should be implemented across all healthcare settings and regularly audited, and surveillance systems strengthened and standardised to allow for comprehensive and consistent reporting of nosocomial transmission of hepatitis across the EU.

Vaccination for coronavirus disease 2019 in liver transplantation candidates should be recommended but not mandated.

Content available: Author Interview and Audio Recording.

Three-phase DNA-origami stepper mechanism based on multi-leg interactions.

Nanoscale stepper motors such as kinesin and dynein play a key role in numerous natural processes such as mitotic spindle formation during cell division or intracellular organelle transport. Their high efficacy in terms of operational speed and processivity has inspired the investigation of biomimetic technologies based on the use of programmable molecules. In particular, several designs of molecular walkers have been explored using DNA nanotechnology. Here, we study the actuation of a DNA-origami walker on a DNA-origami track based on three principles: 1) octapedal instead of bipedal walking for greater redundancy; 2) three pairs of orthogonal sequences, each of which fuels one repeatable stepping phase for cyclically driven motion with controlled directionality based on strain-based step selection; 3) designed size of only 3.5 nm per step on an origami track. All three principles are innovative in the sense that earlier demonstrations of steppers relied on a maximum of four legs on at least four orthogonal sequences to drive cyclic stepping, and took steps much larger than 3.4 nm in size. Using gel electrophoresis and negative-stain electron microscopy, we demonstrate cyclic actuation of DNA-origami structures through states defined by three sets of specific sequences of anchor points. However, this mechanism was not able to provide the intended control over directionality of movement. DNA-origami-based stepper motors will offer a future platform for investigating how increasing numbers of legs can be exploited to achieve robust stepping with relatively small step sizes.

A DCL3 dicing code within Pol IV-RDR2 transcripts diversifies the siRNA pool guiding RNA-directed DNA methylation.

In plants, selfish genetic elements, including retrotransposons and DNA viruses, are transcriptionally silenced by RNA-directed DNA methylation. Guiding the process are short interfering RNAs (siRNAs) cut by DICER-LIKE 3 (DCL3) from double-stranded precursors of ~30 bp that are synthesized by NUCLEAR RNA POLYMERASE IV (Pol IV) and RNA-DEPENDENT RNA POLYMERASE 2 (RDR2). We show that Pol IV's choice of initiating nucleotide, RDR2's initiation 1-2 nt internal to Pol IV transcript ends and RDR2's terminal transferase activity collectively yield a code that influences which precursor end is diced and whether 24 or 23 nt siRNAs are produced. By diversifying the size, sequence, and strand specificity of siRNAs derived from a given precursor, alternative patterns of DCL3 dicing allow for maximal siRNA coverage at methylated target loci.

A Third-Year Medical School Ophthalmology Curriculum for a Longitudinal Integrated Clerkship Model.

Background Longitudinal Integrated Clerkships (LICs) are innovative educational models that allow medical student continuity with patients, preceptors, colleagues, and health care systems. Given their benefits, the number of LICs continues to increase. We share a pilot model for an ophthalmology LIC curriculum at the University of Colorado School of Medicine targeted for students to see patients through transitions of care. Methods A needs assessment was performed including literature search, interviews with expert faculty, and a precurricular student questionnaire. Based on our findings, we developed a pilot two-part curriculum consisting of an introductory lecture and a half-day clinical experience designed to integrate patient eye care into the LIC model. At the end of the year, students completed a questionnaire assessing attitude, confidence, and knowledge. Precourse data were collected from students in the academic year (AY) 2018/2019 to aid with the needs assessment. Postcourse data were collected after completion of the curriculum from students in AY 2019/2020. Data from questionnaire were intended to improve our curricular experience. Results Our curriculum was piloted between the 2019 and 2020 AY. The completion rate of our curriculum was 100%. The questionnaire response rate was 90% in pre- and postcurricular groups ( n =15/17 and n =9/10, respectively). Hundred percent of students from both groups responded that it is "very important"/"important" for all physicians to be able to identify when ophthalmology referral is indicated. After the intervention, there were significant differences in the rate of students responding that they were "confident" diagnosing acute angle-closure glaucoma (36 vs. 78%, p =0.04), treating a chemical burn (20 vs 67%, p =0.02), and diagnosing viral conjunctivitis (27 vs. 67%); 90% of students reported increased confidence in longitudinal care of patients in the eye clinic. Conclusions Medical students believe in the importance of ophthalmic education regardless of their specialty of choice. We present a pilot model to introduce ophthalmology within an LIC model. Future studies with a larger sample are needed to determine the impact of this model in terms of knowledge acquisition and relationship between curriculum and ophthalmology interest among students. Our curriculum can be adapted to other underrepresented specialties in the medical school curriculum and is easily exportable to other LICs.