bluuebunny/crossref_metadata_2025 huggingface dataset:
Retention of stress susceptibility in the mdx mouse model of Duchenne muscular dystrophy after PGC-1α overexpression or ablation of IDO1 or CD38
Authors: Johnson Erynn E , Southern W Michael , Doud Baird , Steiger Brandon , Razzoli Maria , Bartolomucci Alessandro , Ervasti James M
Published: January 2024

Duchenne muscular dystrophy (DMD) is a lethal degenerative muscle wasting disease caused by the loss of the structural protein dystrophin with secondary pathological manifestations including metabolic dysfunction, mood and behavioral disorders. In the mildly affected mdx mouse model of DMD, brief scruff stress causes inactivity, while more severe subordination stress results in lethality. Here, we investigated the kynurenine pathway of tryptophan degradation and the nicotinamide adenine dinucleotide (NAD+) metabolic pathway in mdx mice and their involvement as possible mediators of mdx stress-related pathology. We identified downregulation of the kynurenic acid shunt, a neuroprotective branch of the kynurenine pathway, in mdx skeletal muscle associated with attenuated peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) transcriptional regulatory activity. Restoring the kynurenic acid shunt by skeletal muscle-specific PGC-1α overexpression in mdx mice did not prevent scruff -induced inactivity, nor did abrogating extrahepatic kynurenine pathway activity by genetic deletion of the pathway rate-limiting enzyme, indoleamine oxygenase 1. We further show that reduced NAD+ production in mdx skeletal muscle after subordination stress exposure corresponded with elevated levels of NAD+ catabolites produced by ectoenzyme cluster of differentiation 38 (CD38) that have been implicated in lethal mdx response to pharmacological β-adrenergic receptor agonism. However, genetic CD38 ablation did not prevent mdx scruff-induced inactivity. Our data do not support a direct contribution by the kynurenine pathway or CD38 metabolic dysfunction to the exaggerated stress response of mdx mice.
Modified Commando procedure using a double valve composite through an aorto-annulo-septotomy
Authors: Matsuzaki Kanji , Mitomi Kisato , Imai Akito , Sato Masataka , Watanabe Yasunori
Published: January 2024

Double valve replacement of aortic and mitral valves with intervalvular fibrous body reconstruction (Commando procedure) is a challenging operation. Particularly in redo surgery for prosthetic valve endocarditis, special techniques are needed for approaching and reconstructing the valve complex. We performed a modified Commando procedure using a double valve composite through an aorto-annulo-septotomy. This approach provided a good field of vision at the combined aortic and mitral annuli without incising the left atrial roof. The double valve composite with four-layer patch wings was useful for performing double valve replacement en bloc and aorto-annulo-septotomy closure serially. Using these techniques, we successfully performed the Commando procedure for complicated prosthetic valve endocarditis.
The Ability to Voluntarily Regulate Theta Band Activity Affects How Pharmacological Manipulation of the Catecholaminergic System Impacts Cognitive Control
Authors: Prochnow Astrid , Mückschel Moritz , Eggert Elena , Senftleben Jessica , Frings Christian , Münchau Alexander , Roessner Veit , Bluschke Annet , Beste Christian
Published: January 2024

Background

The catecholaminergic system influences response inhibition, but the magnitude of the impact of catecholaminergic manipulation is heterogeneous. Theoretical considerations suggest that the voluntary modulability of theta band activity can explain this variance. The study aimed to investigate to what extent interindividual differences in catecholaminergic effects on response inhibition depend on voluntary theta band activity modulation.

Methods

A total of 67 healthy adults were tested in a randomized, double-blind, cross-over study design. At each appointment, they received a single dose of methylphenidate or placebo and performed a Go/Nogo task with stimuli of varying complexity. Before the first appointment, the individual’s ability to modulate theta band activity was measured. Recorded EEG data were analyzed using temporal decomposition and multivariate pattern analysis.

Results

Methylphenidate effects and voluntary modulability of theta band activity showed an interactive effect on the false alarm rates of the different Nogo conditions. The multivariate pattern analysis revealed that methylphenidate effects interacted with voluntary modulability of theta band activity at a stimulus processing level, whereas during response selection methylphenidate effects interacted with the complexity of the Nogo condition.

Conclusions

The findings reveal that the individual’s theta band modulability affects the responsiveness of an individual’s catecholaminergic system to pharmacological modulation. Thus, the impact of pharmacological manipulation of the catecholaminergic system on cognitive control most likely depends on the existing ability to self-modulate relevant brain oscillatory patterns underlying the cognitive processes being targeted by pharmacological modulations.
Energy partitioning and controlling factors of evapotranspiration in an alpine meadow in the permafrost region of the Qinghai-Tibet Plateau
Authors: Hu Zhaoyong , Wang Genxu , Sun Xiangyang , Huang Kewei , Song Chunlin , Li Yang , Sun Shouqin , Sun Juying , Lin Shan
Published: January 2024

Energy partitioning and evapotranspiration (ET) of alpine meadows in permafrost areas are crucial for water cycle on the Qinghai-Tibet Plateau. However, seasonal (freeze–thaw cycle) variations in energy partitioning and ET and their driving factors must be clarified. Therefore, 4-year energy fluxes [i.e. latent heat (LE) and sensible heat (H)] were observed, and bulk parameters [i.e. surface conductance, decoupling coefficient (Ω), and Priestley–Taylor coefficient (α)] were estimated in an alpine meadow in the Qinghai-Tibet Plateau. Mean daily LE (27.45 ± 23.89 W/m2) and H (32.51 ± 16.72 W/m2) accounted for 31.71% and 50.14% of available energy, respectively. More available energy was allocated to LE during the rainfall period, while 67.54 ± 28.44% was allocated to H during the frozen period. H was half the LE during rainfall period and seven times the LE during frozen period due to low soil water content and vegetation coverage during the frozen season. Mean annual ET was 347.34 ± 8.39 mm/year, close to mean annual precipitation. Low mean daily Ω (0.45 ± 0.23) and α (0.60 ± 0.29) throughout the year suggested that ET in the alpine meadow was limited by water availability. However, ET was constrained by available energy because of sufficient water supply from precipitation during rainfall season. In contrast, large differences between ET and precipitation indicated that soil water was supplied via lateral flow from melting upstream glaciers and snow during the transition season. The results suggest that seasonal variations in bulk parameters should be considered when simulating water and energy fluxes in permafrost regions.
On the conservation results for local reflection principles
Authors: Kogure Haruka , Kurahashi Taishi
Published: January 2024

For a class $\varGamma $ of formulas, $\varGamma $ local reflection principle $\textrm{Rfn}_{\varGamma }(T)$ for a theory $T$ of arithmetic is a scheme formalizing the $\varGamma $-soundness of $T$. Beklemishev (1997, Theoria, 63, 139–146) proved that for every $\varGamma \in \{\varSigma _{n}, \varPi _{n+1} \mid n \geq 1\}$, the full local reflection principle $\textrm{Rfn}(T)$ is $\varGamma $-conservative over $T + \textrm{Rfn}_{\varGamma }(T)$. We firstly generalize the conservation theorem to nonstandard provability predicates: we prove that the second condition $\textbf{D2}$ of the derivability conditions is a sufficient condition for the conservation theorem to hold. We secondly investigate the conservation theorem in terms of Rosser provability predicates. We construct Rosser predicates for which the conservation theorem holds and Rosser predicates for which the theorem does not hold.
Rapid human genomic DNA cloning into mouse artificial chromosome via direct chromosome transfer from human iPSC and CRISPR/Cas9-mediated translocation
Authors: Miyamoto Hitomaru , Kobayashi Hiroaki , Kishima Nanami , Yamazaki Kyotaro , Hamamichi Shusei , Uno Narumi , Abe Satoshi , Hiramuki Yosuke , Kazuki Kanako , Tomizuka Kazuma , Kazuki Yasuhiro
Published: January 2024

A ‘genomically’ humanized animal stably maintains and functionally expresses the genes on human chromosome fragment (hCF; <24 Mb) loaded onto mouse artificial chromosome (MAC); however, cloning of hCF onto the MAC (hCF-MAC) requires a complex process that involves multiple steps of chromosome engineering through various cells via chromosome transfer and Cre-loxP chromosome translocation. Here, we aimed to develop a strategy to rapidly construct the hCF-MAC by employing three alternative techniques: (i) application of human induced pluripotent stem cells (hiPSCs) as chromosome donors for microcell-mediated chromosome transfer (MMCT), (ii) combination of paclitaxel (PTX) and reversine (Rev) as micronucleation inducers and (iii) CRISPR/Cas9 genome editing for site-specific translocations. We achieved a direct transfer of human chromosome 6 or 21 as a model from hiPSCs as alternative human chromosome donors into CHO cells containing MAC. MMCT was performed with less toxicity through induction of micronucleation by PTX and Rev. Furthermore, chromosome translocation was induced by simultaneous cleavage between human chromosome and MAC by using CRISPR/Cas9, resulting in the generation of hCF-MAC containing CHO clones without Cre-loxP recombination and drug selection. Our strategy facilitates rapid chromosome cloning and also contributes to the functional genomic analyses of human chromosomes.
Rif2 interaction with Rad50 counteracts Tel1 functions in checkpoint signalling and DNA tethering by releasing Tel1 from MRX binding
Authors: Pizzul Paolo , Casari Erika , Rinaldi Carlo , Gnugnoli Marco , Mangiagalli Marco , Tisi Renata , Longhese Maria Pia
Published: January 2024

The yeast Rif2 protein is known to inhibit Mre11 nuclease and the activation of Tel1 kinase through a short motif termed MIN, which binds the Rad50 subunit and simulates its ATPase activity in vitro. The mechanism by which Rif2 restrains Tel1 activation and the consequences of this inhibition at DNA double-strand breaks (DSBs) are poorly understood. In this study, we employed AlphaFold-Multimer modelling to pinpoint and validate the interaction surface between Rif2 MIN and Rad50. We also engineered the rif2-S6E mutation that enhances the inhibitory effect of Rif2 by increasing Rif2-Rad50 interaction. Unlike rif2Δ, the rif2-S6E mutation impairs hairpin cleavage. Furthermore, it diminishes Tel1 activation by inhibiting Tel1 binding to DSBs while leaving MRX association unchanged, indicating that Rif2 can directly inhibit Tel1 recruitment to DSBs. Additionally, Rif2S6E reduces Tel1-MRX interaction and increases stimulation of ATPase by Rad50, indicating that Rif2 binding to Rad50 induces an ADP-bound MRX conformation that is not suitable for Tel1 binding. The decreased Tel1 recruitment to DSBs in rif2-S6E cells impairs DSB end-tethering and this bridging defect is suppressed by expressing a Tel1 mutant variant that increases Tel1 persistence at DSBs, suggesting a direct role for Tel1 in the bridging of DSB ends.
COSMIC: a curated database of somatic variants and clinical data for cancer
Authors: Sondka Zbyslaw , Dhir Nidhi Bindal , Carvalho-Silva Denise , Jupe Steven , Madhumita  , McLaren Karen , Starkey Mike , Ward Sari , Wilding Jennifer , Ahmed Madiha , Argasinska Joanna , Beare David , Chawla Manpreet Singh , Duke Stephen , Fasanella Ilaria , Neogi Avirup Guha , Haller Susan , Hetenyi Balazs , Hodges Leonie , Holmes Alex , Lyne Rachel , Maurel Thomas , Nair Sumodh , Pedro Helder , Sangrador-Vegas Amaia , Schuilenburg Helen , Sheard Zoe , Yong Siew Yit , Teague Jon
Published: January 2024

The Catalogue Of Somatic Mutations In Cancer (COSMIC), https://cancer.sanger.ac.uk/cosmic, is an expert-curated knowledgebase providing data on somatic variants in cancer, supported by a comprehensive suite of tools for interpreting genomic data, discerning the impact of somatic alterations on disease, and facilitating translational research. The catalogue is accessed and used by thousands of cancer researchers and clinicians daily, allowing them to quickly access information from an immense pool of data curated from over 29 thousand scientific publications and large studies. Within the last 4 years, COSMIC has substantially expanded its utility by adding new resources: the Mutational Signatures catalogue, the Cancer Mutation Census, and Actionability. To improve data accessibility and interoperability, somatic variants have received stable genomic identifiers that are associated with their genomic coordinates in GRCh37 and GRCh38, and new export files with reduced data redundancy have been made available for download.
Are Rape Myths ‘Myths’?
Authors: Hayes David J
Published: January 2024

Little attention has been paid to what the word ‘myth’ contributes to the concept of rape myths. Rape myths tend to be regarded as widely believed falsehoods that need to be debunked in order to address patriarchal injustices. This account draws upon a long-standing vernacular English association between myth and falsehood which originated in the Enlightenment. But it is not the only possible definition of myth. This article draws upon mythological studies across a range of disciplines to argue that rape myths should be considered authentically mythic; that is, rape ‘myths’ are culturally significant folk narratives about sexual wrongdoing. This reappraisal enables a shift in our understanding of what rape myths are, what they could be—and what we can do to reduce their pernicious influence on the criminal justice system. It also enables legal scholars to more generally reassess how the concept of ‘myth’ is used across our discipline(s).
Circulating Tumor DNA to Predict Radiographic and Pathologic Response to Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer
Authors: Alden Stephanie L , Lee Valerie , Narang Amol K , Meyer Jeffrey , Gearhart Susan L , Christenson Eric S
Published: January 2024

Despite advances in treatment and response assessment in locally advanced rectal cancer (LARC), it is unclear which patients should undergo nonoperative management (NOM). We performed a single-center, retrospective study to evaluate post-total neoadjuvant therapy (TNT) circulating tumor DNA (ctDNA) in predicting treatment response. We found that post-TNT ctDNA had a sensitivity of 23% and specificity of 100% for predicting residual disease upon resection, with a positive predictive value (PPV) of 100% and a negative predictive value (NPV) of 47%. For predicting poor tumor regression on MRI, ctDNA had a sensitivity of 16% and specificity of 96%, with a PPV of 75% and NPV of 60%. A commercially available ctDNA assay was insufficient to predict residual disease after TNT and should not be used alone to select patients for NOM in LARC.
The zinc finger protein DHHC09 S-acylates the kinase STRK1 to regulate H2O2 homeostasis and promote salt tolerance in rice
Authors: Tian Ye , Zeng Hui , Wu Ji-Cai , Dai Gao-Xing , Zheng He-Ping , Liu Cong , Wang Yan , Zhou Zheng-Kun , Tang Dong-Ying , Deng Guo-Fu , Tang Wen-Bang , Liu Xuan-Ming , Lin Jian-Zhong
Published: January 2024

Soil salinity results in oxidative stress and heavy losses to crop production. The S-acylated protein SALT TOLERANCE RECEPTOR-LIKE CYTOPLASMIC KINASE 1 (STRK1) phosphorylates and activates CATALASE C (CatC) to improve rice (Oryza sativa L.) salt tolerance, but the molecular mechanism underlying its S-acylation involved in salt signal transduction awaits elucidation. Here, we show that the DHHC-type zinc finger protein DHHC09 S-acylates STRK1 at Cys5, Cys10, and Cys14 and promotes salt and oxidative stress tolerance by enhancing rice H2O2-scavenging capacity. This modification determines STRK1 targeting to the plasma membrane or lipid nanodomains and is required for its function. DHHC09 promotes salt signaling from STRK1 to CatC via transphosphorylation, and its deficiency impairs salt signal transduction. Our findings demonstrate that DHHC09 S-acylates and anchors STRK1 to the plasma membrane to promote salt signaling from STRK1 to CatC, thereby regulating H2O2 homeostasis and improving salt stress tolerance in rice. Moreover, overexpression of DHHC09 in rice mitigates grain yield loss under salt stress. Together, these results shed light on the mechanism underlying the role of S-acylation in RLK/RLCK-mediated salt signal transduction and provide a strategy for breeding highly salt-tolerant rice.
Effects of Stimulus Type on 16-kHz Detection Thresholds
Authors: Buss Emily , Kane Stacey G. , Young Kathryn S. , Gratzek Chloe B. , Bishop Danielle M. , Miller Margaret K. , Porter Heather L. , Leibold Lori J. , Stecker G. Christopher , Monson Brian B.
Published: January 2024

Objectives:

Audiometric testing typically does not include frequencies above 8 kHz. However, recent research suggests that extended high-frequency (EHF) sensitivity could affect hearing in natural communication environments. Clinical assessment of hearing often employs pure tones and frequency-modulated (FM) tones interchangeably regardless of frequency. The present study was designed to evaluate how the stimulus chosen to measure EHF thresholds affects estimates of hearing sensitivity.

Design:

The first experiment used standard audiometric procedures to measure 8- and 16-kHz thresholds for 5- to 28-year olds with normal hearing in the standard audiometric range (250 to 8000 Hz). Stimuli were steady tones, pulsed tones, and FM tones. The second experiment tested 18- to 28-year olds with normal hearing in the standard audiometric range using psychophysical procedures to evaluate how changes in sensitivity as a function of frequency affect detection of stimuli that differ with respect to bandwidth, including bands of noise. Thresholds were measured using steady tones, pulsed tones, FM tones, narrow bands of noise, and one-third-octave bands of noise at a range of center frequencies in one ear.

Results:

In experiment 1, thresholds improved with increasing age at 8 kHz and worsened with increasing age at 16 kHz. Thresholds for individual participants were relatively similar for steady, pulsed, and FM tones at 8 kHz. At 16 kHz, mean thresholds were approximately 5 dB lower for FM tones than for steady or pulsed tones. This stimulus effect did not differ as a function of age. Experiment 2 replicated this greater stimulus effect at 16 kHz than at 8 kHz and showed that the slope of the audibility curve accounted for these effects.

Conclusions:

Contrary to prior expectations, there was no evidence that the choice of stimulus type affected school-age children more than adults. For individual participants, audiometric thresholds at 16 kHz were as much as 20 dB lower for FM tones than for steady tones. Threshold differences across stimuli at 16 kHz were predicted by differences in audibility across frequency, which can vary markedly between listeners. These results highlight the importance of considering spectral width of the stimulus used to evaluate EHF thresholds.
Pharmacogenetics at scale in real-world bioresources: CYP2C19 and clopidogrel outcomes in UK Biobank
Authors: Bedair Khaled F. , Smith Blair , Palmer Colin N.A. , Doney Alex S.F. , Pearson Ewan R.
Published: January 2024

Objective

The impact of CYP2C19 genotype on clopidogrel outcomes is one of the most well established pharmacogenetic interactions, supported by robust evidence and recommended by the Food and Drug Administration and clinical pharmacogenetics implementation consortium. However, there is a scarcity of large-scale real-world data on the extent of this pharmacogenetic effect, and clinical testing for the CYP2C19 genotype remains infrequent. This study utilizes the UK Biobank dataset, including 10 365 patients treated with clopidogrel, to offer the largest observational analysis of these pharmacogenetic effects to date.

Methods

Incorporating time-varying drug exposure and repeated clinical outcome, we adopted semiparametric frailty models to detect and quantify exposure-based effects of CYP2C19 (*2,*17) variants and nongenetic factors on the incidence risks of composite outcomes of death or recurrent hospitalizations due to major adverse cardiovascular events (MACE) or hemorrhage in the entire cohort of clopidogrel-treated patients.

Results

Out of the 10 365 clopidogrel-treated patients, 40% (4115) experienced 10 625 MACE events during an average follow-up of 9.23 years. Individuals who received clopidogrel (coverage >25%) with a CYP2C19*2 loss-of-function allele had a 9.4% higher incidence of MACE [incidence rate ratios (IRR), 1.094; 1.044–1.146], but a 15% lower incidence of hemorrhage (IRR, 0.849; 0.712-0.996). These effects were stronger with high clopidogrel exposure. Conversely, the gain-of-function CYP2C19*17 variant was associated with a 5.3% lower incidence of MACE (IRR, 0.947; 0.903–0.983). Notably, there was no evidence of *2 or *17 effects when clopidogrel exposure was low, confirming the presence of a drug-gene interaction.

Conclusion

The impact of CYP2C19 on clinical outcomes in clopidogrel-treated patients is substantial, highlighting the importance of incorporating genotype-based prescribing into clinical practice, regardless of the reason for clopidogrel use or the duration of treatment. Moreover, the methodology introduced in this study can be applied to further real-world investigations of known drug-gene and drug-drug interactions and the discovery of novel interactions.
A Systematic Critical Review of Clinical Pharmacokinetics of Torasemide
Authors: Sherazi Abdul Wasay , Zamir Ammara , Rehman Anees ur , Ashraf Waseem , Imran Imran , Saeed Hamid , Majeed Abdul , Saleem Zikria , Aziz Majid , Alqahtani Faleh , Rasool Muhammad Fawad
Published: January 2024

Purpose:

Torasemide is a potassium-sparing loop diuretic used to treat fluid retention associated with congestive heart failure and kidney and hepatic diseases. This systematic review was conducted to combine all accessible data on the pharmacokinetics (PK) of torasemide in healthy and diseased populations, which may help clinicians avert adverse drug reactions and determine the correct dosage regimen.

Methods:

Four databases were systematically searched to screen for studies associated with the PK of torasemide, and 21 studies met the eligibility criteria. The review protocol was registered in the PROSPERO database (CRD42023390178).

Results:

A decrease in maximum plasma concentration (Cmax) was observed for torasemide after administration of the prolonged-release formulation in comparison to that after administration of the immediate-release formulation, that is, 1.12 ± 0.17 versus 1.6 ± 0.2 mcg/mL. After administering an oral dose of torasemide, a 2-fold increase in the area under the concentration–time curve (AUC) was reported in patients with congestive heart failure compared with the healthy population. Moreover, the patients with renal failure (clearance < 30 mL/min) showed an increase in value of AUC0–∞ that is, 42.9 versus 8.091 mcg.h−1.mL−1 compared with healthy subjects. In addition, some studies have reported interactions with different drugs, in which irbesartan showed a slight increase in the AUC0–∞ of torasemide, whereas losartan and empagliflozin did not.

Conclusions:

The current review summarizes all available PK parameters of torasemide that may be beneficial for avoiding drug–drug interactions in subjects with renal and hepatic dysfunction and for predicting doses in patients with different diseases.
Serum lactate and mean arterial pressure thresholds in patients with cirrhosis and septic shock
Authors: Smith Thomas N. , Choi Chansong , Rattan Puru , Piccolo Serafim Laura , Kassmeyer Blake A. , Lennon Ryan J. , Gajic Ognjen , Olson Jody C. , Kamath Patrick S. , Gallo De Moraes Alice , Simonetto Douglas A.
Published: January 2024

Background:

The Sepsis-3 guidelines have incorporated serum lactate levels of >2 mmol/L in septic shock definition to account for higher observed mortality. Further evidence is needed to support this threshold in cirrhosis, as well as target mean arterial pressure (MAP) during resuscitation.

Methods:

This observational cohort study investigated the association between initial serum lactate and resuscitation MAP levels on in-hospital mortality in patients with and without cirrhosis. Patients admitted to the intensive care unit for the treatment of septic shock between 2006 and 2021 in a quaternary academic center were included. Patients with cirrhosis documented on imaging and International Classification of Disease codes (n=595) were compared to patients without cirrhosis (n=575). The association of intensive care unit admission lactate levels and median 2-hour MAP with in-hospital mortality and the need for continuous renal replacement therapy was assessed. The association between median 24-hour MAP and in-hospital mortality was analyzed post hoc.

Results:

Within the cirrhosis group, admission lactate levels of 2–4 and >4 mmol/L were associated with increased in-hospital mortality compared to lactate <2 mmol/L [adjusted odds ratio (aOR): 1.69, CI: 1.03–2.81, aOR: 4.02, CI: 2.53–6.52]. Median 24-hour MAP 60–65 and <60 mm Hg were also associated with increased in-hospital mortality compared with MAP >65 mm Hg (aOR: 2.84, CI: 1.64–4.92 and aOR: 7.34, CI: 3.17–18.76). In the noncirrhosis group, associations with in-hospital mortality were weaker for lactate 2–4 and >4 mmol/L (aOR: 1.32, CI: 0.77–2.27 and aOR: 2.25, CI: 1.40–3.67) and median 24-hour MAP 60–65 and <60 mm Hg (aOR: 1.70, CI: 0.65–4.14 and aOR: 4.41, CI: 0.79–29.38).

Conclusions:

These findings support utilizing lactate >2 mmol/L in the definition of septic shock, as well as a target MAP of >65 mm Hg during resuscitation in patients with cirrhosis.
The clinical courses of HBV-related acute-on-chronic liver failure and a multi-state model to predict disease evolution
Authors: Yu Xia , Liu Xinxin , Tan Wenting , Wang Xiaobo , Zheng Xin , Huang Yan , Chen Jinjun , Li Beiling , Meng Zhongji , Gao Yanhang , Qian Zhiping , Liu Feng , Lu Xiaobo , Shang Jia , Yan Huadong , Zheng Yubao , Zhang Weituo , Yin Shan , Gu Wenyi , Deng Guohong , Xiang Xiaomei , Zhou Yi , Hou Yixin , Zhang Qun , Xiong Shue , Liu Jing , Chen Ruochan , Long Liyuan , Jiang Xiuhua , Luo Sen , Chen Yuanyuan , Jiang Chang , Zhao Jinming , Ji Liujuan , Mei Xue , Li Jing , Li Tao , Zheng Rongjiong , Zhou Xinyi , Ren Haotang , Sheng Jifang , Li Hai , Shi Yu
Published: January 2024

Background and Aims:

Acute-on-chronic liver failure (ACLF) is a highly dynamic syndrome. The objective of this study was to delineate the clinical course of patients with HBV-ACLF and to develop a model to estimate the temporal evolution of disease severity.

Methods:

We enrolled eligible patients from 2 large, multicenter prospective cohorts. The ACLF grade, organ failures, and outcomes were assessed at multiple time points (days 1/4/7/14/21/28). Probabilities for ACLF transitions between these disease states and to death within 28 days were calculated using a multi-state model that used baseline information and updated ACLF status. The model was validated in independent patients.

Results:

Among all the 445 patients with HBV-ACLF, 76 represented disease progression, 195 had a stable or fluctuating course, 8 with improvement, and the remaining 166 with resolution within 28-day follow-up. New coagulation (63.64%) or renal failure (45.45%) was frequently observed during early progression. Patients with disease progression had a higher incidence of new episodes of ascites [10 (13.16%) vs. 22 (5.96%), p = 0.027] and HE [13(17.11%) vs. 21 (5.69%), p = 0.001], and a significant increase in white blood cell count. The multi-state model represented dynamic areas under the receiver operating characteristic curves ranging from 0.71 to 0.84 for predicting all ACLF states and death at 4, 7, 14, 21, and 28 days post-enrollment and from 0.73 to 0.94 for predicting death alone, performing better than traditional prognostic scores.

Conclusions:

HBV-ACLF is a highly dynamic syndrome with reversibility. The multi-state model is a tool to estimate the temporal evolution of disease severity, which may inform clinical decisions on treatment.
The Tarnished Legacy of a Wonder Drug: Revisiting the Complicated History of Clozapine
Authors: Poudel Roshan , Lerner Barron
Published: January 2024

Anecdotal evidence of superior efficacy and lack of extrapyramidal symptoms in treating schizophrenia made clozapine a promising therapy in the United States during the early 1970s. In 1975, however, numerous fatal cases of clozapine-related agranulocytosis in Finland nearly ended the drug’s development. Convinced of the significant benefits to patients, some clinicians in the United States advocated having clozapine available on a case-by-case humanitarian basis, which eventually helped resurrect the drug for Food and Drug Administration approval in 1989. This article builds on previous literature by utilizing oral histories from clinicians, researchers, and a patient’s family member to understand how clozapine was saved. Exploring these stakeholders’ perspectives has value to modern clinicians, who underprescribe the drug despite demonstrable benefits for treatment-resistant schizophrenia and suicide prevention.
Donut-shaped Corneal Allogeneic Intrastromal Segment as an Alternative to Deep Anterior Lamellar Keratoplasty in Advanced Keratoconus
Authors: Coscarelli Sandro , Coscarelli Sandro P. , Torquetti Leonardo
Published: January 2024

Purpose:

The aim of this study was to describe a new technique of selective corneal stromal transplantation for keratoconus treatment, donut-shaped CAIRS (corneal allogeneic intrastromal ring segment).

Methods:

A donut-shaped corneal graft is obtained using a double-bladed trephine. Descemet membrane, endothelium, and epithelium are all removed from the graft. Only stromal tissue is transplanted. A wide 360-degree intrastromal tunnel is created using the femtosecond laser, with a 30-degree angulation. The diameter is from 5.4 mm to 8 mm optical zone. After dehydration, the corneal graft is inserted into the tunnel. We report the clinical and tomographic outcomes after the procedure in 3 patients.

Results:

The mean follow-up time after donut-shaped CAIRS was 6.01 ± 1.02 months. In case 1, best spectacle–corrected visual acuity improved from 20/150 to 20/40. In case 2, it improved from 20/400 to 20/40, and in case 3 from 20/200 to 20/40. The mean preoperative K was 57.3 ± 4.5 D and reduced to 44.2 ± 2.5 D after donut-shaped CAIRS. The mean spherical equivalent decreased from −9.8 ± 3.2 preoperatively to −3.2 ± 2.2 postoperatively. No intraoperative or postoperative complications were observed. Anterior segment OCT showed a mid-stroma implant, fusiform in shape, equidistant from the epithelium and endothelium.

Conclusions:

Donut-shaped CAIRS is a variation of the traditional CAIRS technique and showed to be an alternative option for keratoconus treatment, especially in moderate to advanced cases with a central clear cornea without scars. The technique is minimally invasive, and the visual axis remains untouched.
Prenatal Lymphedema: A Genotype-Phenotype Analysis
Authors: Ad Michal , Greene Arin K.
Published: January 2024

Primary lymphedema most commonly affects the lower extremities, is progressive, and is not curable. The condition is associated with mutations in approximately 30 genes. Patients usually present with edema during infancy or adolescence. Four of 364 (1%) patients with primary lymphedema in our database were diagnosed by prenatal imaging. Three children did not exhibit lymphedema after birth, 2 had a VEGFC mutation, and 2 exhibited normal lymphatic function by lymphoscintigraphy. Lymphedema identified prenatally is associated with a VEGFC mutation and can resolve postnatally.
Would hyaluronic acid-induced mental bone resorption be a concern? A prospective controlled cohort study and an updated retrospective cohort study
Authors: Guo Xiaoshuang , Zong Xianlei , Song Guodong , Zhao Jingyi , Lai Chenzhi , Zhang Dong , Jin Xiaolei
Published: January 2024

Background:

Hyaluronic acid (HA) is a widely used filler for face contouring and is generally believed to be safe and effective. However, there have been reports of HA-related bone erosion in the chin area without clear scientific data regarding its existence, incidence, and severity. This exploratory study was to evaluate HA-related mental bone resorption through a prospective, controlled, observer-blind, nonrandomized clinical trial and a retrospective cohort study.

Methods:

On the one hand, a prospective, controlled, nonrandomized, single-shot HA-injection clinical trial was conducted. Computed tomographic scans were collected at baseline and at 6–12 months of follow-up for both HA-injection and control groups. On the other hand, an updated retrospective cohort study compared the HA-injection with a blank control group. The primary outcomes composed of three quantitative parameters [bone resorption index (BRIM and BRIN), bone resorption thickness ratio] and one subjective evaluation index (severity ranking). Information about demographics, complications, and injection volume were also recorded.

Results:

From June 2021 to March 2023, 78 patients were prospectively recruited for the study. There was a significant association between HA-injection and bone resorption [BRIM: pre (84.24±8.10%) vs post (79.21±8.70%), P<0.001; BRIN: pre 92.50% (73, 144%) vs 87.99% (63, 132%), P<0.001; bone thickness ratio: HA 24.08% (0, 48%) vs control 0 (0, 17%), P<0.001]. However, there was no difference in large-volume (>1 ml) and small-volume (≦1 ml) injection subgroups [bone resorption thickness ratio: (21.50±10.91%) vs (24.51±11.92%), P=0.350]. The imaging manifestation revealed discernible bone resorption in 35.90% of the patients, with an median bone resorption thickness ratio of 24.08%. Between October of 2019 and March 2023, 95 HA-injection patients (190 semimandibular cases), 95 normal controls were enrolled. The BRIM was significantly lower in the HA-injection group compared to the controls (P<0.001).

Conclusions:

HA may induce bone resorption in the mentum. Large-scale randomized controlled clinical trial is warranted for further confirmation. Patients should be informed of this potential complication.
Patients with early-stage alcohol-associated liver disease are at increased risk of hospital readmission and death
Authors: Aryan Mahmoud , Qian Steve , Chen Zhiguo , Louissaint Jeremy , Qian Xia , Rosenblatt Russell , Verna Elizabeth , Brown Robert , Wong Robert , Clark Virginia , Zhang Wei
Published: January 2024

Background and aims

Patients with alcohol use disorder (AUD) can develop alcohol-associated fatty liver disease (AFLD). However, the impact of AFLD on outcomes remains unclear. We studied the impact of AFLD on readmission, 30-day mortality, and overall mortality in patients admitted with AUD.

Methods

Hospitalized patients with AUD between 2011 and 2019 at a tertiary medical center were retrospectively evaluated. Our population included patients with AUD with AFLD: AST and ALT elevation and serum bilirubin <3 mg/dl. Patients with AUD without evidence of liver disease served as control and were labeled as no ALD. Patients with alcohol-associated cirrhosis (AC) and alcohol-associated hepatitis (AH) were included for comparison. Kaplan–Meier survival analysis and multivariable regression for predictors of mortality and survival were performed.

Results

There were 7522 patients of which 32.44% were female with mean age of 51.86 ± 14.41 years. Patient distribution included no ALD (n = 3775), AFLD (n = 2192), AC (n = 1017) and AH (n = 538) groups. Compared to no ALD group, AFLD group was associated with significantly higher 30-day mortality [4.43% vs. 1.56%, hazard ratio (HR): 2.84; P < 0.001], overall mortality [15.97% vs. 12.69%, HR 1.40, P < 0.001], and 30-day readmission [21.85% vs. 18.49%, odds ratio: 1.21; P < 0.01].

Conclusion

We demonstrated that AFLD is not a benign entity and poses significant mortality risk. Our results suggest that AFLD may be under-recognized and highlight the need for focused management and close follow-up after discharge.
Syphilis prevalence among people living with and without HIV in sub-Saharan Africa: A systematic review and meta-analysis
Authors: Mussa Aamirah , Jarolimova Jana , Ryan Rebecca , Wynn Adrianne , Ashour Dina , Bassett Ingrid V. , Philpotts Lisa L. , Freyne Bridget , Morroni Chelsea , Dugdale Caitlin M.
Published: January 2024

Background

Syphilis is a curable sexually transmitted infection which, untreated, is associated with significant morbidity and mortality. In people living with HIV (PLWH), syphilis carries greater risks of disease progression. We estimated syphilis prevalence among PLWH in the general population in sub-Saharan Africa and compared prevalence among PLWH and without HIV.

Methods

We searched for studies published 1st January 2011 to 28th March 2022 reporting syphilis prevalence among PLWH in sub-Saharan Africa (PROSPERO#: CRD42020167328). We excluded studies in high-risk subpopulations. We estimated pooled syphilis prevalence among PLWH using random effects modelling and compared prevalence to people without HIV when included in the same study. We examined influences of region, study setting, and test type in subgroup analyses.

Results

We identified 926 studies; 53 were included in the meta-analysis. Pooled syphilis prevalence among PLWH was 7.3% (95% CI: 6.3-8.5%). Prevalence differed by region: 3.1% (95% CI: 2.2-4.0%) in Southern, 5.5% (95% CI: 2.3-9.3%) in West/Central, and 10.5% (95% CI: 8.0-13.1%) in Eastern Africa. Prevalence also differed by study setting: 13.8% (95% CI 5.7-23.0%) in SRH/STI care, 8.7% (95% CI 5.0-12.8%) in HIV care, 7.1% (95% CI 5.8-8.5%) in antenatal care and 3.8% (95% CI 2.0-5.8%) household/community-based settings. Syphilis prevalence was higher among PLWH than without HIV (RR: 3.5, 95% CI: 2.8-4.5).

Conclusions

Syphilis is highly prevalent among PLWH in sub-Saharan Africa and is more common among PLWH than without HIV. Integration of syphilis screening and management into HIV care may reduce complications of HIV-syphilis co-infection among PLWH in sub-Saharan Africa.
Development of a proposed organizational framework for undergraduate research training in prosthetics and orthotics education
Authors: Siriwatsopon Juthamas , Samala Manunchaya , Guerra Garry , Kongsatan Pattaraporn , Rayothee Pitchaya
Published: January 2024

Background:

An undergraduate research project gives prosthetic and orthotic (P&O) students the chance to acquire both foundational research knowledge and in-depth knowledge in a specific area of interest in P&O research. Undergraduates frequently enter the field of research with less experience or understanding of research instruments, presenting them with significant obstacles when conducting research.

Objective:

This study's objective was to establish a framework for undergraduate research training in prosthetics and orthotics education.

Methods:

Using narrative qualitative methodology, 4 successive phases of research were conducted. Phase I: A document analysis was conducted to determine the presence of research training in Thailand's undergraduate P&O curriculum taught in 2021; phase II: document analysis of student P&O program feedback reports using manifest content analysis; phase III: strengths, weaknesses, opportunities, and threats analysis of lecturer P&O program feedback reports; and phase IV: data sets from phases I, II, and III were applied to the formulation of a unifying framework. Using grounded theory's three-stage thematic analysis—open, axial, and selective coding—data were analyzed.

Conclusions:

The novel organizational research framework is presented as the result and conclusion of the study. The framework for enhancing this important foundational research program at the undergraduate level was derived through discussion with colleagues and based on the results and discussion from this investigation. Although the framework for undergraduate research training was designed for use by the undergraduate prosthetics and orthotics program in Thailand, it is believed to be applicable and relevant to P&O education worldwide.
Design and characterization of a variable-stiffness ankle-foot orthosis
Authors: Rong Haochen , Ramezani Sepehr , Ambro Alex , Lei Chi Hou , Choi Hwan
Published: January 2024

Background:

Ankle-foot orthoses (AFOs) are a type of assistive device that can improve the walking ability of individuals with neurological disorders. Adjusting stiffness is a common way to customize settings according to individuals' impairment.

Objective:

This study aims to design a variable-stiffness AFO by stiffness module and characterize the AFO stiffness range to provide subject-specific settings for the users.

Methods:

We modeled AFO using bending beams with varying fulcrum positions to adjust the stiffness. To characterize the stiffness range and profile, we used the superposition method to generate the theoretical model to analyze the AFO numerically. The intrinsic deformation of the bending beam in the AFO is considered a combination of 2 bending deformations to replicate actual bending conditions. The corresponding experiments in different fulcrum positions were performed to compare with and optimize the theoretical model. The curve fitting method was applied to tune the theoretical model by adding a fulcrum position–related coefficient.

Results:

The AFO stiffness increased as the fulcrum moved to the proximal position. The maximum stiffness obtained was 1.77 Nm/° at a 6-cm fulcrum position, and the minimum stiffness was 0.82 Nm/° at a 0.5-cm fulcrum position with a 0.43-cm thick fiberglass beam. The corresponding theoretical model had maximum and minimum stiffness of 1.71 and 0.80 Nm/°, respectively. The theoretical model had a 4.08% difference compared with experimental values.

Conclusions:

The stiffness module can provide adjustable stiffness with the fulcrum position and different kinds of fiberglass bars, especially the thickness and material of the beam. The theoretical model with different fulcrum positions can be used to profile the real-time stiffness of the AFO in a dynamic motion and to determine the appropriate dimensions of the bending beam.
Evaluation of the prevention of mother-to-child transmission of HIV programs at the second immunization visit in Burkina Faso and Zambia
Authors: Tassembedo Souleymane , Mwiya Mwiya , Mennecier Anais , Kankasa Chipepo , Fao Paulin , Molès Jean Pierre , Kania Dramane , Chunda-Liyoka Catherine , Sakana Béninwendé Leticia Delphine , D’Ottavi Morgana , Taofiki Ajani Ousmane , Rutagwera David , Wilfred-Tonga Maria Melany , Tylleskär Thorkild , Nagot Nicolas , Van de Perre Philippe ,   for the PROMISE-EPI Study Group∗
Published: January 2024

Objective:

Our study aimed to assess the PMTCT indicators in Burkina Faso and Zambia using a patient-orientated innovative strategy based on the second visit in the Expanded Program on Immunization (EPI-2) visit at 6–8 weeks.

Design:

This was a cross sectional study.

Methods:

We assessed women attending EPI-2 at primary healthcare facilities in Burkina Faso and Zambia with their children about their exposure to PMTCT interventions. For women living with HIV (WLHIV), viral load was measured and their children were tested for HIV DNA using point of care devices.

Results:

Overall, 25 093 were enrolled from Burkina Faso and 8961 women from Zambia. Almost, all women attended at least one antenatal care visit. Among those aware of their HIV-positive status, 95.8 and 99.2% were on antiretroviral therapy (ART) in Burkina Faso and Zambia, respectively. Among WLHIV on ART, 75 and 79.2% achieved a viral load suppression (viral load <1000 copies/ml) in Burkina Faso and Zambia, respectively. Infant postnatal prophylaxis was administered from birth until EPI-2 to 60.9 and 89.7% of HIV-exposed children in Burkina Faso and Zambia, respectively. In Burkina Faso, only 60 of 192 (31.3%) of HIV-exposed children were sampled at day 42 for early infant diagnosis (EID) and 3 (1.6%) received a result by EPI-2. In Zambia, these figures were 879 of 1465 (64.0%) and 9.9% (145/1465), respectively for HIV-exposed children sampled at birth.

Conclusion:

This evaluation strategy at EPI-2 visit could strengthen program monitoring and help identifying gaps to be addressed on the last mile towards elimination of MTCT of HIV.
Improved Indicators for Subnational Unmet Antiretroviral Therapy Need in the Health System: Updates to the Naomi Model in 2023
Authors: Esra Rachel , Mmelesi Mpho , Ketlogetswe Akeem T. , Wolock Timothy M. , Howes Adam , Nong Tlotlo , Matlhaga Matshelo Tina , Ratladi Siphiwe , Ramaabya Dinah , Imai-Eaton Jeffrey W.
Published: January 2024

Background:

Quantifying subnational need for antiretroviral therapy (ART) for HIV is challenging because people living with HIV (PLHIV) access health facilities in areas that may differ from their residence. We defined and demonstrated new indicators for PLHIV treatment needed to guide health system target setting and resource allocation.

Setting:

Botswana.

Methods:

We extended Naomi, a Bayesian small-area model for estimating district-level HIV indicators from national household survey and HIV service delivery data. We used model outputs for ART seeking probabilities in neighboring districts to define the “PLHIV (attending)” indicator representing the estimated number of PLHIV who would seek treatment at health facilities in a district, and “Untreated PLHIV attending” representing gaps in ART service provision. Botswana 2021 district HIV estimates were used to demonstrate new outputs and assess the sensitivity to uncertainty in district population sizes.

Results:

Across districts of Botswana, estimated adult ART coverage in December 2021 ranged 90%–96%. In the capital city Gaborone, there were 50,400 resident PLHIV and 64,200 receiving ART, of whom 24% (95% CI: 20 to 32) were estimated to reside in neighboring districts. Applying ART attendance probabilities gave a “PLHIV attending” denominator of 68,300 and unmet treatment need of 4100 adults (95% CI: 3000 to 5500) for Gaborone health facilities. The facility-based “PLHIV attending” denominator was less-sensitive to fluctuations in district population size assumptions.

Conclusions:

New indicators provided more consistent targets for HIV service provision, but are limited by ART data quality. This challenge will increase as treatment coverage reaches high levels and treatment gaps are smaller.