The impact of dry eye disease on corneal nerve parameters: A systematic review and meta-analysis.

PURPOSE: Dry eye disease (DED) is a growing global health problem with a significant impact on the quality of life of patients. While neurosensory abnormalities have been recognised as a contributor to DED pathophysiology, the potential role of in vivo corneal confocal microscopy in detecting nerve loss or damage remains unclear. This systematic review with meta-analysis (PROSPERO registered CRD42022381861) investigated whether DED has an impact on sub-basal corneal nerve parameters. METHODS: PubMed, Embase and Web of Science Core Collection databases were searched from inception to 9 December 2022. Studies using laser scanning confocal microscopy to compare corneal nerve parameters of DED with healthy eyes were included. Study selection process and data extraction were performed by two independent members of the review team. RESULTS: Twenty-two studies with 916 participants with DED and 491 healthy controls were included, with 21 of these studies included in subsequent meta-analyses. There was a decrease in total corneal nerve length (-3.85 mm/mm2 ; 95% CI -5.16, -2.55), corneal main nerve trunk density (-4.81 number/mm2 ; 95% CI -7.94, -1.68) and corneal nerve branch density (-15.52 number/mm2 ; 95% CI -27.20, -3.84) in DED eyes compared with healthy eyes, with subgroup analysis demonstrating that these differences were more evident in studies using NeuronJ software, a semi-automated procedure. While this review found evidence of loss of corneal nerve parameters in eyes with DED compared with healthy controls, particularly with the use of a semi-automated image analysis method, it is evident that there is substantial heterogeneity between studies in terms of corneal nerve imaging methodology. CONCLUSIONS: Standardisation is required in terms of terminology and analysis, with more research needed to potentially improve the clinical applicability and practicality of corneal nerve imaging. Further investigation is also required to confirm the diagnostic accuracy of this imaging modality and its potential for monitoring DED treatment efficacy.

Racial and Ethnic Disparities in Stillbirth among Pregnant Women with Obesity.

OBJECTIVE: The aim of this study was to examine the relationship between obesity and risk of stillbirth among pregnant women with obesity in the United States, with a focus on racial and ethnic disparities. STUDY DESIGN: We conducted a retrospective cross-sectional analysis of birth and fetal data from the 2014 to 2019 National Vital Statistics System (N = 14,938,384 total births) to examine associations between maternal body mass index (BMI) and risk of stillbirth. Cox's proportional hazards regression model was used to compute adjusted hazard ratios (HR) as a measure of risk of stillbirth in relation to maternal BMI. RESULTS: The stillbirth rate was 6.70 per 1,000 births among women with prepregnancy obesity, while the stillbirth rate among women with a normal (nonobese) prepregnancy BMI was 3.85 per 1,000 births. The risk of stillbirth was greater among women with obesity compared with women without obesity (HR: 1.39; 95% confidence interval [CI]: 1.37-1.41). Compared with non-Hispanic (NH) Whites, women identifying as NH-other (HR: 1.66; 95% CI: 1.61-1.72) and NH-Black (HR: 1.31; 95% CI: 1.26-1.35) were at higher risk of stillbirth, while Hispanic women had a decreased likelihood of stillbirth (HR: 0.38; 95% CI: 0.37-0.40). CONCLUSION: Obesity is a modifiable risk factor for stillbirth. Public health awareness campaigns and strategies targeting weight management in women of reproductive age and racial/ethnic populations at highest risk for stillbirth, are needed. KEY POINTS: · Stillbirth rates differ by race and ethnicity.. · Risk of stillbirth was greatest among women with obesity.. · Stillbirth rates rise with ascending prepregnancy BMI..

Oral and Maxillofacial Injuries Associated With E-Cigarette Explosions: A Systematic Review and Management Guidelines Proposal.

PURPOSE: E-cigarettes have become increasingly popular devices used to consume nicotine in recent years. There is a growing body of evidence regarding the risk of spontaneous explosion of these devices causing burn and projectile injuries. The primary purpose of this review was to summarize all injuries to the oral and maxillofacial region secondary to explosion of e-cigarettes. The secondary purpose was to propose an initial management algorithm for such injuries based on the findings in the literature. This review also aims to test the hypothesis that e-cigarette explosive injuries to the oral region were associated with an increased risk of intubation and surgery and examine whether any other injury pattern was associated with an increased risk of intubation or surgery. METHODS: A cohort study based on identifying cases in the literature was conducted to summarize injuries to the oral and maxillofacial region and examine the associations between injury types and location and management. A literature search of the major biomedical databases was conducted in September 2022 using terms such as e-cigarette, explosion, blast, trauma, and burn, among others, which yielded 922 studies. Nonclinical studies, review articles, and studies without injuries to the facial region were excluded. Study subjects were recorded for demographics, device characteristics, injury mechanism, injury location, management, and complications. Chi-squared analysis was used to determine if the predictor variables of type of injury (burn or projectile) and its associated location (ocular, facial, or intraoral for burns and facial thirds for projectile) were associated with the outcomes of intubation and surgical management. The collected data were then used as a guide to propose an initial management algorithm for these injuries. RESULTS: Twenty eight studies, including 20 case reports and 8 case series met the inclusion criteria. A total of 32 explosions of e-cigarettes to 32 patients caused 105 recorded injuries to the facial region. Projectile injuries made up 73.3% (n = 77) of all facial injuries, while burn injuries made up of 26.7% (n = 28). There were 14 (43.8%) patients who suffered both projectile and burn injuries. Burn injuries mostly involved the face (64.3%, n = 18), oral cavity (25%, n = 7), and eye (10.7%, n = 7). The majority (81.8%, n = 63) of projectile injuries occurred in the lower facial third. There were 20 (62.5%) patients who suffered a bone or tooth fracture. Management of injuries involved surgery in 62.5% (n = 20) of patients, which included open reduction and internal fixation of fractures, dental extraction, bone and skin grafts, and ocular surgery. A complication rate of 44.4% (n = 8) was observed across studies that reported on follow-up. There was no statistically significant association between explosive injury to the oral region and intubation or surgical management. There was also no other statistically significant association between any other injury type and location with intubation or surgical management. CONCLUSIONS: E-cigarettes are at risk for spontaneous combustion that can cause serious oral and maxillofacial injuries, particularly to the lower facial third and commonly requiring surgical management. Safety of these devices should be improved through increased user education and regulation.

Diagnostic accuracy of AS-OCT vs gonioscopy for detecting angle closure: a systematic review and meta-analysis.

PURPOSE: This study aims to review the literature that compares the accuracy of Anterior Segment-Optical Coherence Tomography (AS-OCT) against gonioscopy in detecting eyes with angle closure. It is currently unclear how AS-OCT fits into clinical practice for detecting angle closure. This is a systematic review and meta-analysis. METHODS: A literature search was performed on Medline, Embase, Scopus and the Cochrane Central Register of Controlled Trials to identify studies that investigated the diagnostic accuracy of AS-OCT in detecting eyes with angle closure as diagnosed by gonioscopy. Eligible studies included in the analysis met stringent inclusion criteria determining the sensitivity and specificity of AS-OCT. RESULTS: The initial search identified 727 studies, of which 23 were included in the final analysis. We found substantial variation in the parameters being studied and methodologies. The sensitivity of AS-OCT ranged from 46 to 100% (median 87%). Twenty-one studies identified parameters that showed sensitivity above 80%. The specificity ranged from 55.3 to 100% (median 84%). CONCLUSION: AS-OCT demonstrates good sensitivity for detecting angle closure. It may provide an avenue to address high rates of undiagnosed angle closure, such as found in developing Asian countries. However, AS-OCT is not yet able to replace gonioscopy. Clinicians should consider whether the diagnostic accuracy of AS-OCT is acceptable for their specific clinical use before adopting it. More studies are needed to determine the utility of AS-OCT, including longitudinal studies to determine the significance of eyes classified to have closed angles by AS-OCT but open on gonioscopy.

Drug-drug interactions of Integrase Strand Transfer Inhibitors among older people living with HIV: Interazioni farmacologiche degli inibitori delle integrase tra le persone anziane che vivono con HIV.

The advancement of Human Immunodeficiency Virus (HIV) treatment improves the life expectancy of HIV-positive individuals. People living with HIV have more polypharmacy and drug-drug interactions than those without HIV. Integrase strand transfer inhibitors (INSTIs) are the newest class commonly used for HIV treatment. There are five INSTIs currently approved by the Food and Drug Administration, including raltegravir, elvitegravir, dolutegravir, bictegravir, and cabotegravir. INSTIs class contributes to better safety and efficacy profile, making them the preferred or recommended antiretroviral regimens in HIV treatment guidelines worldwide. Despite the shared mechanism of action, INSTIs differ in pharmacokinetics, contributing to different drug-drug interactions. This review summarized the potential drug interactions of INSTIs and the management of the drug interactions in clinical practice.

Assessing Drug Consumption Rooms and Longer Term (5 Year) Impacts on Community and Clients.

BACKGROUND: Drug consumption rooms (DCRs) and supervised injecting facilities (SIFs) provide a safe environment in which people who inject drugs (PWIDs) can inject under hygienic and supervised conditions. Numerous reviews have documented the benefits of these facilities; however, there is a lack of clarity surrounding their long-term effects. PURPOSE: To conduct, with a systematic approach, a literature review, of published peer-reviewed literature assessing the long-term impacts of DCRs/SIFs. METHODS: A systematic search of the PubMed and Embase database was performed using the keywords: ("SUPERVISED" OR "SAFE*") AND ("CONSUMPTION" OR "INJECT*" OR "SHOOTING") AND ("FACILITY*" OR "ROOM*" OR "GALLERY*" OR "CENTRE*" OR "CENTER*" OR "SITE*"). Included studies were original articles reporting outcomes for five or more years and addressed at least one of the following client or community outcomes; (i) drug-related harms; (ii) access to substance use treatment and other health services; (iii) impact on local PWID population; (iv) impact on public drug use, drug-related crime and violence; and (v) local community attitudes to DCRs. RESULTS: Four publications met our inclusion criteria, addressing four of the five outcomes. Long-term data suggested that while the health of PWID naturally declined over time, DCRs/SIFs helped reduce injecting-related harms. The studies showed that DCRs/SIFs facilitate drug treatment, access to health services and cessation of drug injecting. Local residents and business owners reported less public drug use and public syringe disposal following the opening of a DCR/SIF. CONCLUSION: Long-term evidence on DCRs/SIFs is consistent with established short-term research demonstrating the benefits of these facilities. A relative paucity of studies was identified, with most evidence originating from Sydney and Vancouver. The overall body of evidence would be improved by future studies following outcomes over longer periods and being undertaken in a variety of jurisdictions and models of DCRs/SIFs.

Hyperoxia induces glutamine-fuelled anaplerosis in retinal Müller cells.

Although supplemental oxygen is required to promote survival of severely premature infants, hyperoxia is simultaneously harmful to premature developing tissues such as in the retina. Here we report the effect of hyperoxia on central carbon metabolism in primary mouse Müller glial cells and a human Müller glia cell line (M10-M1 cells). We found decreased flux from glycolysis entering the tricarboxylic acid cycle in Müller cells accompanied by increased glutamine consumption in response to hyperoxia. In hyperoxia, anaplerotic catabolism of glutamine by Müller cells increased ammonium release two-fold. Hyperoxia induces glutamine-fueled anaplerosis that reverses basal Müller cell metabolism from production to consumption of glutamine.

Serine and 1-carbon metabolism are required for HIF-mediated protection against retinopathy of prematurity.

We determined which metabolic pathways are activated by hypoxia-inducible factor 1-mediated (HIF-1-mediated) protection against oxygen-induced retinopathy (OIR) in newborn mice, the experimental correlate to retinopathy of prematurity, a leading cause of infant blindness. HIF-1 coordinates the change from oxidative to glycolytic metabolism and mediates flux through serine and 1-carbon metabolism (1CM) in hypoxic and cancer cells. We used untargeted metabolite profiling in vivo to demonstrate that hypoxia mimesis activates serine/1CM. Both [13C6] glucose labeling of metabolites in ex vivo retinal explants as well as in vivo [13C3] serine labeling of metabolites followed in liver lysates strongly suggest that retinal serine is primarily derived from hepatic glycolytic carbon and not from retinal glycolytic carbon in newborn pups. In HIF-1α2lox/2lox albumin-Cre-knockout mice, reduced or near-0 levels of serine/glycine further demonstrate the hepatic origin of retinal serine. Furthermore, inhibition of 1CM by methotrexate blocked HIF-mediated protection against OIR. This demonstrated that 1CM participates in protection induced by HIF-1 stabilization. The urea cycle also dominated pathway enrichment analyses of plasma samples. The dependence of retinal serine on hepatic HIF-1 and the upregulation of the urea cycle emphasize the importance of the liver to remote protection of the retina.

T4 DNA ligase structure reveals a prototypical ATP-dependent ligase with a unique mode of sliding clamp interaction.

DNA ligases play essential roles in DNA replication and repair. Bacteriophage T4 DNA ligase is the first ATP-dependent ligase enzyme to be discovered and is widely used in molecular biology, but its structure remained unknown. Our crystal structure of T4 DNA ligase bound to DNA shows a compact α-helical DNA-binding domain (DBD), nucleotidyl-transferase (NTase) domain, and OB-fold domain, which together fully encircle DNA. The DBD of T4 DNA ligase exhibits remarkable structural homology to the core DNA-binding helices of the larger DBDs from eukaryotic and archaeal DNA ligases, but it lacks additional structural components required for protein interactions. T4 DNA ligase instead has a flexible loop insertion within the NTase domain, which binds tightly to the T4 sliding clamp gp45 in a novel α-helical PIP-box conformation. Thus, T4 DNA ligase represents a prototype of the larger eukaryotic and archaeal DNA ligases, with a uniquely evolved mode of protein interaction that may be important for efficient DNA replication.

Inflammation-Responsive Drug-Conjugated Dextran Nanoparticles Enhance Anti-Inflammatory Drug Efficacy.

Stimuli-responsive nanoparticles (NPs) are especially interesting to enhance the drug delivery specificity for biomedical applications. With the aim to achieve a highly stable and inflammation-specific drug release, we designed a reactive oxygen species (ROS)-responsive dextran-drug conjugate (Nap-Dex). By blending Nap-Dex with the acid-sensitive acetalated dextran polymer, we achieved a dual-responsive NP with high specificity toward the inflammatory environment. The inflammatory environment not only has elevated ROS levels but also has a lower pH than healthy tissues, making pH and ROS highly suitable triggers to target inflammatory diseases. The anti-inflammatory cyclooxygenase inhibitor naproxen was modified with an ROS-responsive phenylboronic acid (PBA) and conjugated onto dextran. The dextran units were functionalized with up to 87% modified naproxen. This resulted in a complete drug release from the polymer within 20 min at 10 mM H2O2. The dual-responsive NPs reduced the levels of the proinflammatory cytokine IL-6 120 times more efficiently and TNFα 6 times more efficiently than free naproxen from lipopolysaccharide (LPS)-activated macrophages. These additional anti-inflammatory effects were found to be mainly attributed to ROS-scavenging effects. In addition, the model cargo fluorescein diacetate was released in an LPS-induced inflammatory response in vitro. We believe that drug conjugation using PBA can be applied to various drugs and dextran-based materials for enhanced drug efficacy, where this work demonstrates the significance of functionalized carbohydrates polymer-drug conjugates.

A Single-Flask Synthesis of α-Alkylidene and α-Benzylidene Lactones from Ethoxyacetylene, Epoxides/Oxetanes, and Carbonyl Compounds.

Low temperature treatment of (ethoxyethynyl)lithium with epoxides or oxetanes in the presence of BF3•OEt2, followed by addition of aldehydes or ketones and warming to room temperature, affords structurally diverse five- and six-membered α-alkylidene and α-benzylidene lactones (5) in good to excellent yields. This one-pot process, in which three new carbon-carbon bonds and a ring are formed, affords substituted α,ß-unsaturated lactones of predominantly Z-configuration. The reaction likely occurs via alkyne-carbonyl metathesis of a hydroxy-ynol ether intermediate, acid-promoted alkene E- to Z-isomerization, and lactonization.

Lewis acid catalyzed intramolecular condensation of ynol ether-acetals. Synthesis of alkoxycycloalkene carboxylates.

Treatment of ynol ether-tethered dialkyl acetals with catalytic quantities of scandium triflate in CH(3)CN gives rise to five-, six-, and seven-membered alkoxycycloalkene carboxylates in good to excellent yields. Tri- and tetrasubstituted carbocyclic and heterocyclic alkenes may be formed by this method, and the products obtained may serve as useful intermediates for natural product synthesis.

Intramolecular [2 + 2] cycloaddition reactions of alkynyl ether derived ketenes. A convenient synthesis of donor-acceptor cyclobutanes.

Mild thermolysis of tert-butyl alkynyl ethers furnishes aldoketenes, which undergo facile [2 + 2] cycloaddition reactions with pendant di- and trisubstituted alkenes. A wide variety of cis-fused cyclobutanones are produced in moderate to high diastereoselectivity and good to excellent yields by this method, and free hydroxyl groups are tolerated in the ene-ynol ether starting materials. Enol-ynol ethers also undergo efficient reaction to produce donor-acceptor cyclobutanes in high yields.

Benefit finding, affective reactions to diabetes stress, and diabetes management among early adolescents.

OBJECTIVE: To examine whether benefit finding was associated with better adjustment among adolescents with diabetes by buffering negative affective reactions to diabetes stress and by promoting positive affective reactions. DESIGN: Early adolescents aged 10-14 with Type 1 diabetes (n = 252) described recent diabetes stressors, affective reactions, and perceived coping effectiveness. They also completed measures of benefit finding, depressive symptoms, and adherence. Metabolic control (i.e., HbA1c) was obtained from medical records. MAIN OUTCOME MEASURES: The main outcome measures were perceived coping effectiveness, depressive symptoms, adherence, and HbA1c. RESULTS: Benefit finding was associated with lower depressive symptoms, higher perceived coping effectiveness and better adherence, and with higher positive as well as negative affective reactions to diabetes stress. Benefit finding interacted with negative affective reactions to predict depressive symptoms and HbA1c. Negative affective reactions to stress were associated with poorer adjustment among those with low benefit finding, but were unrelated or more weakly related to poor adjustment among those with high benefit finding. Positive affective reactions did not mediate associations between benefit finding and any outcome. CONCLUSIONS: Consistent with a stress-buffering process, benefit finding may be a resource that buffers the disruptive aspects of negative affective reactions to stress for adolescents' diabetes management.