bluuebunny/crossref_metadata_2025 huggingface dataset:
MADDD-seq, a novel massively parallel sequencing tool for simultaneous detection of DNA damage and mutations
Authors: Vermulst Marc , Paskvan Samantha L , Chung Claire S , Franke Kathryn , Clegg Nigel , Minot Sam , Madeoy Jennifer , Long Annalyssa S , Gout Jean-Francois , Bielas Jason H
Published: August 2024

Our genome is exposed to a wide variety of DNA-damaging agents. If left unrepaired, this damage can be converted into mutations that promote carcinogenesis or the development of genetically inherited diseases. As a result, researchers and clinicians require tools that can detect DNA damage and mutations with exceptional sensitivity. In this study, we describe a massively parallel sequencing tool termed Mutation And DNA Damage Detection-seq (MADDD-seq) that is capable of detecting O6-methyl guanine lesions and mutations simultaneously, with a single assay. To illustrate the dual capabilities of MADDD-seq, we treated WT and DNA repair deficient yeast cells with the DNA-damaging agent MNNG and tracked DNA lesions and mutations over a 24-h time period. This approach allowed us to identify thousands of DNA adducts and mutations in a single sequencing run and gain deep insight into the kinetics of DNA repair and mutagenesis.
A phage satellite manipulates the viral DNA packaging motor to inhibit phage and promote satellite spread
Authors: Boyd Caroline M , Seed Kimberley D
Published: August 2024

ICP1, a lytic bacteriophage of Vibrio cholerae, is parasitized by phage satellites, PLEs, which hijack ICP1 proteins for their own horizontal spread. PLEs' dependence on ICP1’s DNA replication machinery and virion components results in inhibition of ICP1’s lifecycle. PLEs are expected to depend on ICP1 factors for genome packaging, but the mechanism(s) PLEs use to inhibit ICP1 genome packaging is currently unknown. Here, we identify and characterize Gpi, PLE’s indiscriminate genome packaging inhibitor. Gpi binds to ICP1’s large terminase (TerL), the packaging motor, and blocks genome packaging. To overcome Gpi's negative effect on TerL, a component PLE also requires, PLE uses two genome packaging specifiers, GpsA and GpsB, that specifically allow packaging of PLE genomes. Surprisingly, PLE also uses mimicry of ICP1’s pac site as a backup strategy to ensure genome packaging. PLE’s pac site mimicry, however, is only sufficient if PLE can inhibit ICP1 at other stages of its lifecycle, suggesting an advantage to maintaining Gpi, GpsA and GpsB. Collectively, these results provide mechanistic insights into another stage of ICP1’s lifecycle that is inhibited by PLE, which is currently the most inhibitory of the documented phage satellites. More broadly, Gpi represents the first satellite-encoded inhibitor of a phage TerL.
Genetic–epigenetic interplay in the determination of plant 3D genome organization
Authors: He Xiaoning , Dias Lopes Chloé , Pereyra-Bistrain Leonardo I , Huang Ying , An Jing , Chaouche Rim Brik , Zalzalé Hugo , Wang Qingyi , Ma Xing , Antunez-Sanchez Javier , Bergounioux Catherine , Piquerez Sophie , Fragkostefanakis Sotirios , Zhang Yijing , Zheng Shaojian , Crespi Martin , Mahfouz Magdy M , Mathieu Olivier , Ariel Federico , Gutierrez-Marcos Jose , Li Xingwang , Bouché Nicolas , Raynaud Cécile , Latrasse David , Benhamed Moussa
Published: August 2024

The 3D chromatin organization plays a major role in the control of gene expression. However, our comprehension of the governing principles behind nuclear organization remains incomplete. Particularly, the spatial segregation of loci with similar repressive transcriptional states in plants poses a significant yet poorly understood puzzle. In this study, employing a combination of genetics and advanced 3D genomics approaches, we demonstrated that a redistribution of facultative heterochromatin marks in regions usually occupied by constitutive heterochromatin marks disrupts the 3D genome compartmentalisation. This disturbance, in turn, triggers novel chromatin interactions between genic and transposable element (TE) regions. Interestingly, our results imply that epigenetic features, constrained by genetic factors, intricately mold the landscape of 3D genome organisation. This study sheds light on the profound genetic-epigenetic interplay that underlies the regulation of gene expression within the intricate framework of the 3D genome. Our findings highlight the complexity of the relationships between genetic determinants and epigenetic features in shaping the dynamic configuration of the 3D genome.
KREH2 helicase represses ND7 mRNA editing in procyclic-stage Trypanosoma brucei by opposite modulation of canonical and ‘moonlighting’ gRNA utilization creating a proposed mRNA structure
Authors: Meehan Joshua , Ivens Alasdair , Grote Scott , Rodshagen Tyler , Chen Zihao , Goode Cody , Sharma Sunil K , Kumar Vikas , Frese Addison , Goodall Zachary , McCleskey Laura , Sechrist Rebecca , Zeng Lanying , Savill Nicholas J , Rouskin Silvi , Schnaufer Achim , McDermott Suzanne M , Cruz-Reyes Jorge
Published: August 2024

Unknown factors regulate mitochondrial U-insertion/deletion (U-indel) RNA editing in procyclic-form (PCF) and bloodstream-form (BSF) T. brucei. This editing, directed by anti-sense gRNAs, creates canonical protein-encoding mRNAs and may developmentally control respiration. Canonical editing by gRNAs that specify protein-encoding mRNA sequences occurs amid massive non-canonical editing of unclear sources and biological significance. We found PCF-specific repression at a major early checkpoint in mRNA ND7, involving helicase KREH2-dependent opposite modulation of canonical and non-canonical ‘terminator’ gRNA utilization. Terminator-programmed editing derails canonical editing and installs proposed repressive structure in 30% of the ND7 transcriptome. BSF-to-PCF differentiation in vitro recreated this negative control. Remarkably, KREH2-RNAi knockdown relieved repression and increased editing progression by reverting canonical/terminator gRNA utilization. ND7 transcripts lacking early terminator-directed editing in PCF exhibited similar negative editing control along the mRNA sequence, suggesting global modulation of gRNA utilization fidelity. The terminator is a ‘moonlighting’ gRNA also associated with mRNA COX3 canonical editing, so the gRNA transcriptome seems multifunctional. Thus, KREH2 is the first identified repressor in developmental editing control. This and our prior work support a model whereby KREH2 activates or represses editing in a stage and substrate-specific manner. KREH2’s novel dual role tunes mitochondrial gene expression in either direction during development.
Loss of DNA glycosylases improves health and cognitive function in a C. elegans model of human tauopathy
Authors: Tiwari Vinod , Buvarp Elisabeth , Borbolis Fivos , Puligilla Chandrakala , Croteau Deborah L , Palikaras Konstantinos , Bohr Vilhelm A
Published: August 2024

Alzheimer's disease (AD) is a neurodegenerative disorder representing a major burden on families and society. Some of the main pathological hallmarks of AD are the accumulation of amyloid plaques (Aβ) and tau neurofibrillary tangles. However, it is still unclear how Aβ and tau aggregates promote specific phenotypic outcomes and lead to excessive oxidative DNA damage, neuronal cell death and eventually to loss of memory. Here we utilized a Caenorhabditis elegans (C. elegans) model of human tauopathy to investigate the role of DNA glycosylases in disease development and progression. Transgenic nematodes expressing a pro-aggregate form of tau displayed altered mitochondrial content, decreased lifespan, and cognitive dysfunction. Genetic ablation of either of the two DNA glycosylases found in C. elegans, NTH-1 and UNG-1, improved mitochondrial function, lifespan, and memory impairment. NTH-1 depletion resulted in a dramatic increase of differentially expressed genes, which was not apparent in UNG-1 deficient nematodes. Our findings clearly show that in addition to its enzymatic activity, NTH-1 has non-canonical functions highlighting its modulation as a potential therapeutic intervention to tackle tau-mediated pathology.
Relative Effectiveness of the MF59-Adjuvanted Influenza Vaccine Versus High-Dose Influenza Vaccine in Older Adults With Influenza Risk Factors During the 2019–2020 US Influenza Season
Authors: Imran Mahrukh , Mills Carrie W , McDermott Kimberly W , Dean Alex , Bogdanov Alina , McGovern Ian , Haag Mendel D M
Published: August 2024

Background

This study estimated the relative vaccine effectiveness (rVE) of the MF59-adjuvanted trivalent influenza vaccine (aTIV) versus high-dose trivalent inactivated influenza vaccine (HD-TIV) for prevention of influenza-related medical encounters (IRMEs) during the 2019–2020 United States (US) influenza season stratified by the cumulative number of influenza risk factors. A secondary objective evaluated outpatient IRMEs and influenza- and pneumonia-related hospitalizations.

Methods

This retrospective cohort study included US adults ≥65 years old vaccinated with aTIV or HD-TIV between 1 August 2019 and 31 January 2020. Electronic health records linked to claims were used to ascertain exposure, covariates, risk factors, and outcomes. Multivariable adjusted odds ratios (ORs) were derived using inverse probability of treatment–weighted samples to calculate rVEs independently for individuals with 0, ≥1, 1–2, or ≥3 risk factors.

Results

The study included 1 115 725 aTIV and 2 561 718 HD-TIV recipients. For the primary outcome of any IRME, the analysis found comparable effectiveness between aTIV and HD-TIV (rVE, 5.2% [95% confidence interval {CI}, −5.9% to 15.1%]) among those with 0 risk factors, whereas aTIV was more effective than HD-TIV among patients with ≥1, 1–2, or ≥3 risk factors (12.5% [95% CI, 10.0%–15.0%], 18.4% [95% CI, 13.7%–22.9%], and 10.4% [7.4%–13.3%], respectively). The same trends were observed for the secondary outcomes.

Conclusions

This study demonstrated comparable effectiveness of aTIV and HD-TIV among individuals with no identified risk factors and higher effectiveness of aTIV compared with HD-TIV in preventing any IRMEs, outpatient IRMEs, and influenza- or pneumonia-related hospitalizations among those with at least 1 or multiple high-risk factors in adults ≥65 years old.
Radiation and outflow properties of super-Eddington accretion flows around various mass classes of black holes: Dependence on the accretion rates
Authors: Yoshioka Shogo , Mineshige Shin , Ohsuga Ken , Kawashima Tomohisa , Kitaki Takaaki
Published: August 2024

We perform axisymmetric two-dimensional radiation-hydrodynamic simulations of super-Eddington accretion flow and outflow around black holes to examine the properties of radiation and outflow as functions of the black hole mass and the accretion rate on to the black hole ($\dot{M}_{\rm BH}$). We find that the $\dot{m}_{\rm BH} ({\equiv} \dot{M}_{\rm BH}c^2 /L_{\rm Edd})$ dependence of $L_{\rm rad}/L_{\rm Edd}$ and $L_{\rm mech}/L_{\rm Edd}$ found for a stellar-mass black hole can apply to the high-mass cases, where $L_{\rm rad}$ is the radiation luminosity, $L_{\rm mech}$ is the mechanical luminosity, c is the speed of light, and $L_{\rm Edd}$ is the Eddington luminosity. Such universalities can appear in the regime in which electron scattering opacity dominates over absorption opacity. Further, the normalized isotropic mechanical luminosity $L_{\rm mech}^{\rm ISO}/L_{\rm Edd}$ (evaluated by normalized density and velocity at $\theta =10^\circ$) exhibits a broken power-law relationship with ${\dot{m}}_{\rm BH}$; $L_{\rm mech}^{\rm ISO}/ L_{\rm Edd} \propto {\dot{m}}_{\rm BH}^{2.7}$ (or $\propto {\dot{m}}_{\rm BH}^{0.7}$) below (above) ${\dot{m}}_{\rm BH}\sim 400$. This is because the radial velocity stays nearly constant (or even decreases) below (above) the break with increase of $\dot{m}_{\rm BH}$. We also find that the luminosity ratio is $L_{\rm mech}/L_{\rm rad}^{\rm ISO} \sim 0.05$ at ${\dot{m}}_{\rm BH} \sim 100$, which is roughly consistent with the observations of NLS1, 1H 0323+103.
Leaf transcriptomes from C3, C3-C4 intermediate, and C4Neurachne species give insights into C4 photosynthesis evolution
Authors: Lauterbach Maximilian , Bräutigam Andrea , Clayton Harmony , Saladié Montserrat , Rolland Vivien , Macfarlane Terry D , Weber Andreas P M , Ludwig Martha
Published: August 2024

The C4 photosynthetic pathway is hypothesized to have evolved from the ancestral C3 pathway through progressive changes in leaf anatomy and biochemistry with extant C3-C4 photosynthetic intermediate species representing phenotypes between species demonstrating full C3 and full C4 states. The Australian endemic genus Neurachne is the only known grass group that contains distinct, closely related species that carry out C3, C3-C4 intermediate, or C4 photosynthesis. To explore and understand the molecular mechanisms underlying C4 photosynthesis evolution in this genus, leaf transcriptomes were generated from two C3, three photosynthetic intermediate (proto-Kranz, C2-like, and C2), and two C4Neurachne species. The data were used to reconstruct phylogenetic relationships in Neurachne, which confirmed two independent C4 origins in the genus. Relative transcript abundances substantiated the photosynthetic phenotypes of individual species and highlighted transcriptional investment differences between species, including between the two C4 species. The data also revealed proteins potentially involved in C4 cycle intermediate transport and identified molecular mechanisms responsible for the evolution of C4-associated proteins in the genus.
Evaluation of changes in cardiac longitudinal strain rate in patients with systemic sclerosis undergoing iloprost treatment: an observational study
Authors: Isaia Ivan , Aparo Paola , Castelletti Federica , Regolo Matteo , Aprile Maria Letizia , Fiorenza Paolo , Sambataro Gianluca , Malatino Lorenzo , Colaci Michele
Published: August 2024

Objectives

SSc is characterized by widespread microangiopathy and fibrosis of skin and visceral organs. Left ventricle involvement is usually subclinical, characterized by systolic and/or diastolic dysfunction. The global longitudinal strain (GLS), a validated and reliable technique for the measurement of ventricular longitudinal deformation by means of echocardiography, may detect subclinical systolic dysfunction of SSc myocardium. The improvement of myocardial perfusion by means of intravenous Iloprost administration could ameliorate the contractility of SSc heart. Therefore, we aimed to evaluate GLS in a series of SSc patients prior and after Iloprost infusion.

Methods

Fifteen consecutive SSc patients (age: 54 ± 11 years; 12 females) treated with Iloprost because of the presence/history of digital ulcers underwent echocardiography, including GLS technique. This evaluation was conducted immediately before Iloprost administration and at the end of the 6-h infusion session.

Results

Significant improvement in the mean GLS was observed after Iloprost administration (from −13.5 ± 2.5 to −15 ± 3.3; P = 0.011). The echocardiographic data obtained from the four-chamber view showed the best quality for GLS analysis and showed a highly significant improvement of the strain after Iloprost administration (from −13.4 ± 2.2 to −15.6 ± 3; P = 0.001). The degree of GLS improvement did not correlate with any SSc parameters.

Conclusion

Iloprost administration improved GLS, suggesting that the increase of myocardial perfusion allowed, at least in part, a correction of left ventricular systolic dysfunction. Further studies are needed to confirm these findings, further exploring the mid/long-term effects of Iloprost on myocardial contraction.
Factors associated with long-term opioid use among patients with axial spondyloarthritis or psoriatic arthritis who initiate opioids
Authors: Huang Yun-Ting , Jenkins David A , Yimer Belay Birlie , Jani Meghna
Published: August 2024

Objective

Up to one in five patients with axial spondyloarthritis (AxSpA) or psoriatic arthritis (PsA) newly initiated on opioids transition to long-term use within the first year. This study aimed to investigate individual factors associated with long-term opioid use among opioid new users with AxSpA/PsA.

Methods

Adult patients with AxSpA/PsA and without prior cancer who initiated opioids between 2006 and 2021 were included from Clinical Practice Research Datalink Gold, a national UK primary care database. Long-term opioid use was defined as having ≥3 opioid prescriptions issued within 90 days, or ≥90 days of opioid supply, in the first year of follow-up. Individual factors assessed included sociodemographic, lifestyle factors, medication use and comorbidities. A mixed-effects logistic regression model with patient-level random intercept was used to examine the association of individual characteristics with the odds of long-term opioid use.

Results

In total, 10 300 opioid initiations were identified from 8212 patients (3037 AxSpA; 5175 PsA). The following factors were associated with long-term opioid use: being a current smoker (OR: 1.62; 95%CI: 1.38,1.90), substance use disorder (OR: 2.34, 95%CI: 1.05,5.21), history of suicide/self-harm (OR: 1.84; 95%CI: 1.13,2.99), co-existing fibromyalgia (OR: 1.62; 95%CI: 1.11,2.37), higher Charlson Comorbidity Index (OR: 3.61; 95%CI: 1.69,7.71 for high scores), high MME/day at initiation (OR: 1.03; 95%CI: 1.02,1.03) and gabapentinoid (OR: 2.35; 95%CI: 1.75,3.16) and antidepressant use (OR: 1.69; 95%CI: 1.45,1.98).

Conclusions

In AxSpA/PsA patients requiring pain relief, awareness of lifestyle, sociodemographic and prescribing characteristics associated with higher risk of long-term opioid use can prompt timely interventions such as structured medication reviews and smoking cessation to promote safer prescribing and better patient outcomes.
Demyelination and impaired oligodendrogenesis in the corpus callosum following lead exposure
Authors: Liu Luke L , Emir Uzay , Gu Huiying , Sang Lara T , Sawiak Stephen J , Cannon Jason R , Du Yansheng , Zheng Wei
Published: August 2024

The corpus callosum is an oligodendrocyte-enriched brain region, replenished by newborn oligodendrocytes from oligodendrocyte progenitor cells (OPCs) in subventricular zone (SVZ). Lead (Pb) exposure has been associated with multiple sclerosis, a disease characterized by the loss of oligodendrocytes. This study aimed to investigate the effects of Pb exposure on oligodendrogenesis in SVZ and myelination in the corpus callosum. Adult female mice were used for a disproportionately higher prevalence of multiple sclerosis in females. Acute Pb exposure (one ip-injection of 27 mg Pb/kg as PbAc2 24 hr before sampling) caused mild Pb accumulation in the corpus callosum. Ex vivo assay using isolated SVZ tissues collected from acute Pb-exposed brains showed a diminished oligodendrogenesis in SVZ-derived neurospheres compared with controls. In vivo subchronic Pb exposure (13.5 mg Pb/kg by daily oral gavage 4 wk) revealed significantly decreased newborn BrdU+/MBP+ oligodendrocytes in the corpus callosum, suggesting demyelination. Mechanistic investigations indicated decreased Rictor in SVZ OPCs, defective self-defense pathways, and reactive gliosis in the corpus callosum. Given the interwined pathologies between multiple sclerosis and Alzheimer’s disease, the effect of Pb on myelination was evaluated in AD-modeled APP/PS1 mice. Myelin MRI on mice following chronic exposure (1,000 ppm Pb in drinking water as PbAc2 for 20 wk) revealed a profound demyelination in the corpus callosum compared with controls. Immunostaining of the choroid plexus showed diminished signaling molecule (Klotho, OTX2) expressions in Pb-treated animals. These observations suggest that Pb caused demyelination in the corpus callosum, likely by disrupting oligodendrogenesis from SVZ OPCs. Pb-induced demyelination represents a crucial pathogenic pathway in Pb neurotoxicity, including multiple sclerosis.
Mixtures of phthalates disrupt expression of genes related to lipid metabolism and peroxisome proliferator-activated receptor signaling in mouse granulosa cells
Authors: Alahmadi Hanin , Martinez Stephanie , Farrell Rivka , Bikienga Rafiatou , Arinzeh Nneka , Potts Courtney , Li Zhong , Warner Genoa R
Published: August 2024

Phthalates are a class of known endocrine-disrupting chemicals that are found in common everyday products. Several studies associate phthalate exposure with detrimental effects on ovarian function, including growth and development of the follicle and production of steroid hormones. We hypothesized that dysregulation of the ovary by phthalates may be mediated by phthalate toxicity towards granulosa cells, a major cell type in ovarian follicles responsible for key steps of hormone production and nourishing the developing oocyte. To test the hypothesis that phthalates target granulosa cells, we harvested granulosa cells from adult CD-1 mouse ovaries and cultured them for 96 h in vehicle control, a phthalate mixture, or a phthalate metabolite mixture (0.1 to 100 μg/ml). After culture, we measured metabolism of the phthalate mixture into monoester metabolites by the granulosa cells, finding that granulosa cells do not significantly contribute to ovarian metabolism of phthalates. Immunohistochemistry of phthalate metabolizing enzymes in whole ovaries confirmed that these enzymes are not strongly expressed in granulosa cells of antral follicles and that ovarian metabolism of phthalates likely occurs primarily in the stroma. RNA sequencing of treated granulosa cells identified 407 differentially expressed genes, with overrepresentation of genes from lipid metabolic processes, cholesterol metabolism, and peroxisome proliferator-activated receptor (PPAR) signaling pathways. Expression of significantly differentially expressed genes related to these pathways was confirmed using qPCR. Our results agree with previous findings that phthalates and phthalate metabolites have different effects on the ovary, but both interfere with PPAR signaling in granulosa cells.
Recent warming and increasing CO2 stimulate growth of dominant trees under no water limitation in South Korea
Authors: Arco Molina Julieta Gabriela , Saurer Matthias , Altmanova Nela , Treydte Kerstin , Dolezal Jiri , Song Jong-Suk , Altman Jan
Published: August 2024

Increases in temperatures and atmospheric CO2 concentration influence the growth performance of trees worldwide. The direction and intensity of tree growth and physiological responses to changing climate do, however, vary according to environmental conditions. Here we present complex, long-term, tree-physiological responses to unprecedented temperature increase in East Asia. For this purpose, we studied radial growth and isotopic (δ13C and δ18O) variations using tree-ring data for the past 100 yr of dominant Quercus mongolica trees from the cool-temperate forests from Hallasan, South Korea. Overall, we found that tree stem basal area increment, intercellular CO2 concentration and intrinsic water-use efficiency significantly increased over the last century. We observed, however, short-term variability in the trends of these variables among four periods identified by change point analysis. In comparison, δ18O did not show significant changes over time, suggesting no major hydrological changes in this precipitation-rich area. The strength and direction of growth–climate relationships also varied during the past 100 yr. Basal area increment (BAI) did not show significant relationships with the climate over the 1924–1949 and 1975–1999 periods. However, over 1950–1974, BAI was negatively affected by both temperature and precipitation, while after 2000, a temperature stimulus was observed. Finally, over the past two decades, the increase in Q. mongolica tree growth accelerated and was associated with high spring–summer temperatures and atmospheric CO2 concentrations and decreasing intrinsic water-use efficiency, δ18O and vapour pressure deficit, suggesting that the photosynthetic rate continued increasing under no water limitations. Our results indicate that the performance of dominant trees of one of the most widely distributed species in East Asia has benefited from recent global changes, mainly over the past two decades. Such findings are essential for projections of forest dynamics and carbon sequestration under climate change.
Enhancing sleep quality for adult patients
Authors: Winegar Rhonda
Published: August 2024

Sleep is critical to a person's physiological and psychological functioning. Approximately 30% to 40% of the general population experiences insomnia, and among patients with mental health conditions, the prevalence of insomnia and other sleep disturbances rises to about 70%. Insomnia is associated with many adverse health issues, including lower immunity, weight gain, elevated BP, and increased mortality, and it is often undiagnosed and either untreated or self-treated. Providers can work together with patients to enact measures—such as implementation of enhanced sleep hygiene, engagement in cognitive behavioral therapy, and treatment of any underlying causes—that can markedly improve patient sleep quality. This article provides an overview of evidence-based best practices and whole-person strategies that NPs can adopt to address poor sleep quality in adult patients, and it serves as a primer for primary care NPs on common presentations of several sleep disorders.
Supervised Disulfiram Should Be Considered First-line Treatment for Alcohol Use Disorder
Authors: Holt Stephen R.
Published: August 2024

Despite the prevalence of alcohol use disorder (AUD) in the United States, the armamentarium of FDA-approved medications available for AUD treatment is remarkably small. Disulfiram, 1 of only 3 approved medications, is consistently designated as a second-line option in national treatment guidelines, citing inconsistent evidence, lack of patient preference, and safety concerns. These concerns, however, stem from a misguided interpretation of the evidence that exclusively relies upon double-blind randomized controlled trials (RCT). When viewed instead as both a medication and a behavioral intervention, open-label RCTs become a more appropriate research method, yielding overwhelmingly favorable efficacy data for disulfiram, and supervised disulfiram, in particular. With these data in mind, supervised disulfiram should be redesignated as a first-line intervention in both treatment guideline creation and clinical pathway tools. The addiction medicine community can no longer afford to neglect this critical therapeutic resource.
Induction to Methadone 80 mg in the First Week of Treatment of Patients Who Use Fentanyl: A Case Series From an Outpatient Opioid Treatment Program
Authors: Steiger Scott , McCuistian Caravella , Suen Leslie W. , Shapiro Brad , Tompkins D. Andrew , Bazazi Alexander R.
Published: August 2024

Objectives

Current guidelines for methadone titration may unnecessarily delay reaching effective doses for patients using fentanyl, resulting in an increased risk of ongoing fentanyl use, dissatisfaction with treatment, and early dropout. Development and evaluation of rapid methadone induction protocols may improve treatment for patients using fentanyl.

Methods

Retrospective chart review was conducted for patients admitted in 2022 to a single licensed opioid treatment program (OTP) where a rapid induction protocol provides methadone 40 mg on day 1, 60 mg on day 2, and 80 mg on day 3 to patients using fentanyl <65 years old without significant medical comorbidities. The primary feasibility outcome was completion of the protocol, defined by receipt of methadone dose 80 mg or more on treatment day 7. The primary safety outcomes were oversedation, nonfatal overdose, and death. A secondary outcome was retention in treatment at 30 days.

Results

Rapid induction was ordered for 93 patients and completed by 65 (70%). Average dose on day 7 for patients who completed was 89 mg (SD 9.5 mg) versus 49 mg (SD 14.0 mg) for those who did not. No episodes of oversedation, nonfatal overdose, or death were observed. At 30 days, 85% of the patients who had the rapid protocol ordered (79/93) were retained, with 88% (57/65) who completed the protocol retained versus 79% (22/28) who did not complete (OR 1.9, 95% CI 0.6–6.2).

Conclusions

Rapid induction to methadone 80 mg by day 7 was feasible for outpatients using fentanyl in this study at a single OTP. No significant safety events were identified.
Complex Fractures of the Radial and Ulnar Shaft
Authors: Lynch Thomas B. , Sabbag Casey M. , Wilson David J. , Plucknette Benjamin F.
Published: August 2024

Successful management of radial and ulnar shaft fractures is an essential skill for all orthopaedic surgeons. The frequent presentation of these injuries coupled with the nuanced anatomic considerations that must be observed for successful outcomes dictate that these injuries require a thorough understanding by the treating surgeon. Intraoperative care to restore the anatomic radial bow and rotation is essential for the resumption of functional forearm rotation postinjury. Often, problems arising during the operative treatment of radial and ulnar shaft fractures come in predictable patterns that can be mitigated with preoperative planning and sound technique. Cases of increased complexity with segmental bone defects and soft tissue defects require a variety of advanced reconstructive techniques.
Reverse Essex-Lopresti and Other Forms of Longitudinal Forearm Instability
Authors: Heifner John J. , Mercer Deana M.
Published: August 2024

Longitudinal forearm instability is a consequence of interosseous ligament complex disruption. Radiographic identifiers should alert the surgeon to the disrupted structures. Understanding the injury pattern can simplify the treatment process. The clinical presentation will vary based on the involved interosseous ligament components. The surgeon should aim to restore the anatomic radioulnar relationship and then address the remaining pathology as needed. The central band is the foundational structure that maintains this relationship and should be addressed in each injury pattern when disrupted. In this study, we describe rare forms of longitudinal forearm instability.
“Scarfrodesis”—Simultaneously Addressing Hallux Valgus and Hallux Rigidus With a Scarf Osteotomy and First Metatarsophalangeal Joint Arthrodesis: A Case Report
Authors: Moore David , Shet Sahil S. , O’Neill Barry
Published: August 2024

This case report described a novel procedure used to address a concomitant hallux valgus and hallux rigidus in a patient in her sixties with rheumatoid arthritis. Initial radiographs confirmed concomitant severe hallux valgus deformity with first metatarsophalangeal joint osteoarthritis. A scarf osteotomy was performed followed by a first metatarsophalangeal joint arthrodesis in what the authors have called a “Scarfrodesis” procedure. At 1-, 2-, and 3-year follow-ups, the patient had complete resolution of pain, no limitation in mobility, and had complete consolidation of her arthrodesis. Her AOFAS Hallux Metatarsophalangeal-Interphalangeal Scale Score improved from 29 preoperatively to 72 at 1-year and 3-year follow-ups, with improvement in her Visual Analog Scale and SF-36 at 3-year follow-up. The authors advocate the use of this simple but elegant procedure, which has not been described in addressing the dual pathology in this cohort.
Tumor necrosis factor ALPHA Inhibitor Associated Köhlmeier–Degos Disease as a Novel Iatrogenic Paradigm That Underscores Excessive Type I Interferon in Its Pathogenesis
Authors: Magro Cynthia M. , Sanders Scott
Published: August 2024

Malignant atrophic papulosis/Köhlmeier–Degos disease was first described in 1941 by Köhlmeier in an anecdotal case report that described a young man who presented with extensive multiple intestinal perforations and a papular skin rash. Köhlmeier–Degos disease represents a unique vasculopathy targeting both the microvasculature and the arterial system. One of its most characteristic features is reflected by the discrete multifocal depressed porcelain lesions involving the skin and gastrointestinal tract. The pathological findings are striking and can be broadly categorized into those that are vascular in nature versus extravascular matrix production in the context of extensive extravascular hyaluronic acid and collagen deposition. A dynamic evolutionary morphology is observed not only clinically but also histologically. The microvascular alterations are particularly evident in the skin and are characterized by endothelial cell necrosis with subsequent endothelial cell detachment accompanied by intraluminal fibrin deposition, defining a thrombogenic microangiopathy that in later stage lesions is typically pauci-inflammatory. The arterial lesions are very distinctive and include significant neointimal proliferation with vascular luminal occlusion by amorphous plugs of collagen intimately admixed with platelets. Pathogenetically enhanced type I interferon signaling and endothelial cell injury mediated by the membranolytic attack complex (ie, C5b-9) are key in the evolution of the thrombotic microvascular and obliterative fibrosing arteriopathic changes. We describe a case of Köhlmeier–Degos disease that developed in the setting of tumor necrosis factor (TNF)-alpha inhibitor therapy with the drug golimumab. The clinical features, light microscopic findings, and a pathophysiologic paradigm based on the critical role of TNF-alpha in controlling the type I interferon response are discussed.
Pseudo-random Number Generator Influences on Average Treatment Effect Estimates Obtained with Machine Learning
Authors: Naimi Ashley I. , Yu Ya-Hui , Bodnar Lisa M.
Published: August 2024

Background:

The use of machine learning to estimate exposure effects introduces a dependence between the results of an empirical study and the value of the seed used to fix the pseudo-random number generator.

Methods:

We used data from 10,038 pregnant women and a 10% subsample (N = 1004) to examine the extent to which the risk difference for the relation between fruit and vegetable consumption and preeclampsia risk changes under different seed values. We fit an augmented inverse probability weighted estimator with two Super Learner algorithms: a simple algorithm including random forests and single-layer neural networks and a more complex algorithm with a mix of tree-based, regression-based, penalized, and simple algorithms. We evaluated the distributions of risk differences, standard errors, and P values that result from 5000 different seed value selections.

Results:

Our findings suggest important variability in the risk difference estimates, as well as an important effect of the stacking algorithm used. The interquartile range width of the risk differences in the full sample with the simple algorithm was 13 per 1000. However, all other interquartile ranges were roughly an order of magnitude lower. The medians of the distributions of risk differences differed according to the sample size and the algorithm used.

Conclusions:

Our findings add another dimension of concern regarding the potential for “p-hacking,” and further warrant the need to move away from simplistic evidentiary thresholds in empirical research. When empirical results depend on pseudo-random number generator seed values, caution is warranted in interpreting these results.
Nrf2 Ameliorates Atrial Fibrosis During Antithrombotic Therapy for Atrial Fibrillation by Modulating CYP2C9 Activity
Authors: Wu Liting , Li Zhumeng , Xu Lijuan , Fan Yingchao , Mao Delong , Sun Hanxiao , Zhuang Wenfang
Published: August 2024

Anticoagulant therapy can significantly reduce the incidence of stroke and peripheral embolism events in patients with atrial fibrillation (AF). Although warfarin is widely used as an anticoagulant drug, a wrong dose can lead to increased risks of bleeding or blood clots. The aim of this study was to assess whether nuclear factor–erythroid-2–related factor 2 (Nrf2) can improve the efficacy of warfarin through the regulation of cytochrome P450 family 2 subfamily C member 9 (CYP2C9) using a rat model of AF. Results showed that AF significantly reduced Nrf2 in myocardial tissue of sham-operated rats. Furthermore, Nrf2 overexpression effectively reduced AF-induced atrial fibrosis by reducing collagen in the left atrium, inhibiting the expression of the fibrosis-related genes collagen I and transforming growth factor-β1 in rats with AF. Nrf2 overexpression can activate CYP2C9, decrease the serum concentration of warfarin, and decrease prothrombin time and international normalized ratio in AF rats. In this article, Nrf2 overexpression protects against fibrosis, increased survival in AF rats, and activated CYP2C9 expression, thus broadening the therapeutic range of warfarin in AF rats.
A Comparison of Capsular Contracture Rates after Immediate Implant-based Breast Reconstruction Using Biologic versus Synthetic Mesh
Authors: Ferenz Sarah , Bai Jennifer , Fracol Megan , Kim John Y.S.
Published: August 2024

Background:

Capsular contracture is one of the most common reasons for reoperation after implant-based breast reconstruction. Prior investigations have suggested that biologic mesh may mitigate capsular contracture development. This study sought to compare capsular contracture rates between patients undergoing immediate implant-based breast reconstruction with biologic versus synthetic mesh.

Methods:

A retrospective review was conducted of the senior author’s primary implant-based breast reconstructions between 2008 and 2023. Demographics and the incidence of clinically significant Baker grade III or IV capsular contractures were compared between biologic and synthetic mesh cohorts. Univariate and multivariate logistic regressions were then performed to assess potential risk factors for the development of capsular contracture.

Results:

A total of 772 breasts underwent immediate reconstruction, of which 689 (89.2%) used biologic and 83 (10.8%) used synthetic mesh. Capsular contracture occurred in 15 (2.2%) biologic mesh breasts and three (3.6%) synthetic mesh breasts with no significant difference between the two groups (P = 0.430). Logistic regression showed that radiation was a borderline significant risk factor for developing capsular contracture, but the use of either biologic or synthetic mesh was not significant (P = 0.351).

Conclusions:

Biologic and synthetic meshes function as effective tools in prosthetic breast reconstruction. Our long-term data suggest that the risk of capsular contracture with these devices is low, and there does not seem to be a difference between the two materials. However, there does need to be a shift in how capsular contracture is assessed and discussed in the reconstruction population.
Evolving Role of Exosomes in Plastic and Reconstructive Surgery and Dermatology
Authors: McGraw Ian T. , Wilson Erin Elise , Behfar Atta , Paradise Christopher R. , Rohrich Rod J. , Wyles Saranya P.
Published: August 2024

Exosomes, or extracellular vesicles, represent the latest cell-free addition to the regenerative medicine toolkit. In vitro preclinical studies have demonstrated the safety and efficacy of exosomes, which vary based on source and biomanufacturing, for a myriad of potential therapeutic applications relevant to skin and soft tissue reconstruction. Primary search was performed in September 2021 on the MEDLINE database via PubMed and Ovid, with focus on articles about therapeutic application of exosomes or extracellular vesicles. In total, 130 articles met criteria for applicability, including early-stage clinical trials, preclinical research studies with in vivo application, and articles applicable to plastic and reconstructive surgery and dermatology. Most studies used animal models of human disease processes, using either animal donor cells to isolate exosomes, or human donor cells in animal models. Exosome technology has catapulted as an acellular therapeutic vehicle with off-the-shelf accessibility. These features eliminate prior threshold for broad adoption of regenerative cell-based therapies into surgical and medical practice. To date, there are no exosome products approved by the US Food and Drug Administration. This review highlights exosomes as the new frontier in regenerative medicine and outlines its preclinical therapeutic applications for cutaneous repair and restoration.
Thigh Perforator Exchange: Intraflap Perforator Augmentation of Anterolateral Thigh Free Flaps
Authors: Palines Patrick A. , Nungesser Matthew E. , Baudoin Morgan E. , Melancon Devin M. , Stalder Mark W.
Published: August 2024

Peripheral perfusion in large anterolateral thigh flaps may be inadequate if perforator zones are not properly planned during flap design and harvest, and variations in vascular anatomy can contribute to operative difficulty and morbidity. Intraflap anastomosis of extrinsic perforators may allow for augmentation of perfusion while avoiding significant intramuscular dissection. Adaptation of the perforator exchange technique, previously described in autologous breast reconstruction, optimizes vascular flow in anterolateral thigh flaps. Here, we present a technique for intraflap perforator anastomosis (the thigh perforator exchange) and illustrate its use in a subset of patients. This technique is relatively simple and rapid to perform with no vascular complications observed in our series.
NOVEL AGENTS IN THE MANAGEMENT OF DIABETES AND RISK OF WORSENING DIABETIC RETINOPATHY
Authors: Rajagopal Rithwick , McGill Janet B.
Published: August 2024

Purpose:

Novel therapies for diabetes have potent effects on glycemic control, obesity, and cardiovascular risk reduction, but some, including the popular drug semaglutide, have also been implicated in worsening of diabetic retinopathy (DR). Given the ubiquity of these new agents, understanding the risks to vision is important. Here, we review the data for several newly available agents in terms of systemic efficacy and retinal safety.

Methods:

Literature review.

Results:

Novel antihyperglycemic treatments include incretin mimetics and enhancers, sodium-glucose cotransporter inhibitors, long-acting insulins, and insulin delivery systems. All improve glycemic control, and some have been shown to reduce major cardiovascular outcomes. In a pivotal trial, semaglutide was associated with approximately 75% increased risk of DR worsening. The novel long-acting insulin icodec, formulated for once weekly dosing, showed increased risk of DR worsening over a once daily insulin. No other recent antihyperglycemic agent was associated with DR worsening, although following the semaglutide trials, nearly all studies excluded patients with preexisting DR. Cases of DR worsening were rare in all instances. Dedicated safety studies for semaglutide in DR are currently underway.

Conclusion:

For most patients being considered for treatment with a novel antihyperglycemic agent, benefits on systemic metabolic and cardiovascular health are very likely to outweigh potential retinal harms. Although the true risks of the new agents on DR are unclear because their safety data come from secondary end points, the most vulnerable patients are those with preexisting high-risk DR, poor baseline glycemic control, and using insulin.
Neurotrophic corneal melt after deep anterior lamellar keratoplasty
Authors: McAlinden Colm , Matsou Artemis
Published: August 2024

Introduction:

This case report features the management of a challenging case of neurotrophic keratopathy (NK). Important considerations in the management of epithelial defects in neurotrophic eyes after corneal transplantation are discussed.

Patient and Clinical Findings:

A 73-year-old man was referred for management of secondary microbial keratitis on a background of neurotrophic herpes simplex keratitis in the left eye. Acinetobacter parvus was identified and treated. After the resolution of the infection, a residual central corneal scar was significantly affecting vision; therefore, an 8-mm deep anterior lamellar keratoplasty (DALK) was performed 3 years later.

Diagnosis, Intervention, and Outcomes:

After DALK, a large central epithelial defect occurred, and this progressed to graft melt with a descemetocele. An emergency tectonic DALK was performed along with an amniotic membrane, bandage contact lens, and lateral temporary tarsorrhaphy. No epithelial defect or further melt was observed in the postoperative period, including after removal of the tarsorrhaphy, and at 9 months postoperatively, the graft remains clear with no epithelial defect.

Conclusions:

In NK, frank epithelial defects, especially after corneal transplantation, require careful consideration. Immediate management options including amniotic membrane transplantation and tarsorrhaphy should be considered to reduce the risk of progression to corneal melting.
Erector Spinae Plane Block Reduces Postoperative Pain and Narcotic Utilization Compared With Transversus Abdominis Plane Block After Cystectomy With Urinary Diversion
Authors: Igel Daniel A. , Martin Austin , Sullivan Peter , Wyre Hadley W. , Mirza Moben , Taylor John A. , Holzbeierlein Jeffrey M. , Thompson Jeffrey , Pozek John-Paul , Lee Eugene K.
Published: August 2024

Background:

Regional analgesia is a critical component of enhanced recovery after surgery pathways for cystectomy, but there is little research comparing different modalities. Transversus abdominis plane block is a well-established procedure used for postoperative regional analgesia, whereas erector spinae plane block is a recently described technique that some contend improves pain control.

Objective:

We sought to compare these modalities in patients undergoing cystectomy, with primary end points of pain scores and total narcotic utilization measured in morphine milliequivalents.

Methods:

We retrospectively reviewed 77 consecutive patients who underwent open radical cystectomy. Patients who did not undergo erector spinae plane block or transversus abdominis plane block or who used chronic narcotics were excluded. Pain intensity scores were measured immediately postoperatively and in 24-hour intervals until 72 hours postoperatively. Cumulative narcotic utilization at 72 hours, return to bowel function, and length of stay were measured.

Results:

Fifty-one patients met inclusion criteria. Seventeen patients underwent erector spinae plane block and 34 transversus abdominis plane block. Erector spinae plane block patients reported lower pain scores immediately postoperatively (P = .046), at 48 hours (P = .019), and 72 hours (P = .019). Erector spinae plane block patients used less narcotics after 72 hours than transversus abdominis plane block patients (median: 62.50 morphine milliequivalents vs 146.25 morphine milliequivalents, P = .008).

Conclusions:

Compared with transversus abdominis plane block, erector spinae plane block reduced total narcotic utilization by 234% while also reducing subjective patient pain scores. Increased adoption of erector spinae plane block could have major impacts on both clinical outcomes and patient satisfaction in patients undergoing radical cystectomy.
Robot-Assisted Laparoscopic Reverse 7 Ileal Ureter and Bladder Augmentation: A Complex Urological Case
Authors: Nigro Noah N. , Bhalla Rohan G. , Flynn Brian J.
Published: August 2024

A 51-year-old male with acute myeloid leukemia status post total body radiation and stem cell transplant complicated by BK cystitis and renal insufficiency presented to our clinic for evaluation and management of bilateral ureteral strictures. He was found to have a small capacity bladder and an approximately 5F distal right ureteral stricture as well as an obliterated distal stricture left ureteral stricture. After counseling on a variety of management options, we mutually decided to pursue robot-assisted laparoscopic bladder augmentation with bilateral ureteral reconstruction using a reverse 7 ileal ureter technique. Surgery proceeded without complication. The patient’s JP drain was removed on postoperative day 5. He was discharged with bilateral PCNs, ureteral stents, and a Foley catheter. His Foley was removed at 3 weeks postoperatively. Postoperative renal ultrasound and renogram demonstrated bilaterally patulous renal collecting systems without obstruction. At 12-months follow-up, the patient has maintained renal function and is able to void per his urethra without obstruction or incontinence. We’ve shown that robot-assisted laparoscopic reverse 7 ileal ureter is a safe and effective option for management of bilateral ureteral strictures.