bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of the 2023–2024 Formulation of the COVID-19 Messenger RNA Vaccine
Authors: Shrestha Nabin K , Burke Patrick C , Nowacki Amy S , Gordon Steven M
Published: March 2024

Background

The purpose of this study was to evaluate whether the 2023–2024 formulation of the coronavirus disease 2019 (COVID-19) messenger RNA vaccine protects against COVID-19.

Methods

Cleveland Clinic employees when the 2023–2024 formulation of the COVID-19 messenger RNA vaccine became available to employees were included. Cumulative incidence of COVID-19 over the following 17 weeks was examined prospectively. Protection provided by vaccination (analyzed as a time-dependent covariate) was evaluated using Cox proportional hazards regression, with time-dependent coefficients used to separate effects before and after the JN.1 lineage became dominant. The analysis was adjusted for the propensity to get tested, age, sex, pandemic phase when the last prior COVID-19 episode occurred, and the number of prior vaccine doses.

Results

Among 48 210 employees, COVID-19 occurred in 2462 (5.1%) during the 17 weeks of observation. In multivariable analysis, the 2023–2024 formula vaccinated state was associated with a significantly lower risk of COVID-19 before the JN.1 lineage became dominant (hazard ratio = .58; 95% confidence interval [CI] = .49–.68; P < .001), and lower risk but one that did not reach statistical significance after (hazard ratio = .81; 95% CI = .65–1.01; P = .06). Estimated vaccine effectiveness was 42% (95% CI = 32–51) before the JN.1 lineage became dominant, and 19% (95% CI = −1–35) after. Risk of COVID-19 was lower among those previously infected with an XBB or more recent lineage and increased with the number of vaccine doses previously received.

Conclusions

The 2023–2024 formula COVID-19 vaccine given to working-aged adults afforded modest protection overall against COVID-19 before the JN.1 lineage became dominant, and less protection after.
Empowering left-behind places in Southwest China: participation in coffee value chains as place-based development
Authors: Qian Junxi , Zeng Yuan , Tang Xueqiong , Hu Xiaohui
Published: March 2024

Geographical scholarship has advocated the importance of endogenous and place-sensitive development to levelling up left-behind places, by means of reactivating untapped potentials and recuperating a sense of belonging. Drawing on the approaches of global value chain (GVC), and to a lesser extent, global production network (GPN), this paper rethinks how GVC/GPN participation articulates with endogenous assets and enhances local actors’ capacities to achieve economic and social upgrading. We present a case study of the coffee economy in Lujiang Township, Yunnan Province, China. We find that local villagers are able to tap into opportunities of learning and upgrading, but these processes are mediated by institutions and moral economies. Ultimately, economic empowerment translates into the revival of a sense of belonging.
Social play in African savannah elephants may inform selection against aggression
Authors: Norscia Ivan , Hecker Martin , Caselli Marta , Collarini Edoardo , Gallego Aldama Beatriz , Borragán Santos Santiago , Cordoni Giada
Published: March 2024

In social groups, competition for individual advantage is balanced with cooperation, for the collective benefit. Selection against aggression has favored cooperation and non-aggressive competitive strategies. Because social play is a behavioral system that fluctuates between cooperation and competition, selection against aggression might have especially influenced this behavior. African savannah elephants (Loxodonta africana) are a low aggressive species, therefore suitable to investigate this aspect. We collected all occurrences observational audio-video data on social play, aggression/threats, and affiliation on an African elephant colony housed in a 25-ha open space at Parque de la Naturaleza de Cabarceno (Cantabria, Spain) and composed of 4 family groups (3 immature males, 3 immature females, and 7 adult females) and 2 adult males. Anticipating the influence of reduced aggression, we found that social play decreased with age, persisting in adults, and that it was highest in males. Social play was associated with affiliation (informing cooperation). Indeed, individuals that were central in the social play network were also central in the affiliation network. For immature subjects, we found a correlation between social play and affiliation sociomatrices. However, such correlation was absent in adults and social play mostly occurred between families. Despite the limitations related to dealing with a small captive group, this study largely supports the idea that the features of social play in African savannah elephants may be related to low aggression. This investigation hints toward a non-purely cooperative use of play, possibly as a non-aggressive interaction that accommodates different levels of cooperation and competition.
Spatial Single Cell Profiling Using Imaging Mass Cytometry: Inflammatory Versus Penetrating Crohn’s Disease
Authors: Lehmann Malte , Weixler Benjamin , Elezkurtaj Sefer , Loddenkemper Christopher ,   TRR241 IBDome Consortium, Atreya Imke , Atreya Raja , Bacher Petra , Becker Christoph , Bojarski Christian , Britzen-Laurent Nathalie , Bosch-Voskens Caroline , Chang Hyun-Dong , Diefenbach Andreas , Günther Claudia , Hegazy Ahmed N , Hildner Kai , Klose Christoph S N , Koop Kristina , Krug Susanne , Kühl Anja A , Leppkes Moritz , López-Posadas Rocío , Ludwig Leif S H , Neufert Clemens , Neurath Markus , Patankar Jay , Prüß Magdalena , Radbruch Andreas , Romagnani Chiara , Ronchi Francesca , Sanders Ashley , Scheffold Alexander , Schulzke Jörg-Dieter , Schumann Michael , Schürmann Sebastian , Siegmund Britta , Stürzl Michael , Trajanoski Zlatko , Triantafyllopoulou Antigoni , Waldner Maximilian , Weidinger Carl , Wirtz Stefan , Zundler Sebastian , Kühl Anja A , Siegmund Britta
Published: March 2024

Background and Aims

Fistula formation is a major complication in Crohn’s disease [CD] and the role of the immune cell compartment remains to be elucidated. Thus, we compared the immune cell compartment of CD fistula to inflammatory CD colitis using imaging mass cytometry [IMC] and immunofluorescence.

Methods

A 36-marker panel including structural, functional, and lineage markers for use in IMC was established. This panel was applied to analyse paraffin-embedded CD fistula tract [n = 11], CD colitis [n = 10], and colon samples from non-inflamed controls [n = 12]. Computational methods for cell segmentation, dimensionality reduction, and cell type clustering were used to define cell populations for cell frequency, marker distribution, and spatial neighbourhood analysis. Multiplex immunofluorescence was used for higher resolution spatial analysis.

Results

Analysis of cell frequencies in CD fistulas compared to CD colitis and control colonic samples revealed a significant increase in neutrophils, effector cytotoxic T cells, and inflammatory macrophages in CD fistula samples, whereas regulatory T cells were decreased. Neutrophils in CD fistula expressed significantly more matrix metalloproteinase 9 [MMP9], correlating with extracellular matrix remodelling. Neighbourhood analysis revealed a strong association between MMP9+ neutrophils and effector cytotoxic T cells in both CD fistulas and colitis.

Conclusions

This study presents the first highly multiplexed single cell analysis of the immune cell compartment of CD fistulas and their spatial context. It links immune cell dynamics, particularly MMP9+ neutrophils, to extracellular matrix remodelling in CD fistulas, offering insights into the complex network of cellular interactions and potential therapeutic targets for CD complications.
The transatlantic divide: intermediary liability, free expression, and the limits of trade harmonization
Authors: Liu Han-Wei
Published: March 2024

Amid escalating apprehensions surrounding content regulation, the USA has discreetly integrated provisions reminiscent of its Communications Decency Act Section 230 (CDA 230) into trade agreements, offering broad immunity. This scholarly analysis critically assesses this manoeuvre by juxtaposing such CDA 230-like provisions against the UK’s established legal framework governing online content and freedom of expression. Utilizing a comparative legal methodology, the paper underscores the pronounced differences between the USA and UK stances on intermediary liability for third-party content, moulded by their unique constitutional foundations and jurisprudential interpretations of free speech rights. The insertion of CDA 230-aligned clauses into trade agreements poses a potential threat to the UK’s nuanced equilibrium between safeguarding free speech and upholding other paramount interests, such as privacy and reputation. An scrutiny of UK defamation statutes and content regulation protocols reveals inherent challenges in transplanting CDA 230 provisions into trade contexts. In summation, the paper ardently supports a diversified approach to online content governance and cautions against standardizing intermediary liability laws via trade agreements, especially between nations with divergent foundational beliefs. It fervently endorses a cross-disciplinary discourse involving both trade and legal specialists to ensure the preservation of free expression while concurrently recognizing the intricacies of crafting universally applicable standards for online platforms and content regulation.
Biology, distribution and conservation of a dwarf-group crayfish, Euastacus spinichelatus Morgan, 1997 (Decapoda: Astacidea: Parastacidae), a freshwater crayfish from the Great Dividing Range, New South Wales, Australia
Authors: McCormack Robert B , Whiterod Nick S
Published: March 2024

We present the outcomes of two conservation initiatives, namely ‘The Australian Crayfish’ and ‘Saving the Spinys’ projects, which have substantially contributed to enhancing our understanding of E. spinichelatus concerning its distribution, habitat, biology, and conservation status. We extend the range of E. spinichelatus to encompass the headwater reaches of the Namoi River within the Murray-Darling Basin. The use of molecular taxonomy analyses identified divergent lineages that acted to remove the southeastern tributaries of the Hastings River and the most western tributary of the Manning River from the range of E. spinichelatus. The species has suffered significant population declines in recent years, with it appearing to be highly susceptible to anthropogenic changes, drought and/or high-severity bushfires. Results advocate for the classification of E. spinichelatus as an endangered species, recognizing its distinctive ecological niche and its status as a climate refugee, aiming to protect this rare species from anthropogenic and climate-related challenges. We also present a taxonomic key differentiating E. spinichelatus from other members of Parastacidae in the region.
Quasi-2D inversion of surface large fixed-loop transient electromagnetic sounding data
Authors: Li Feng-Ping , Yue Jian-Hua , Yang Hai-Yan , Wu Yun , Liu Zhi-Xin , Jiang Zhi-Hai
Published: March 2024

In many cases, 1D inversion is still an important step in transient electromagnetic data processing. Potential issues may arise in the calculation of apparent resistivity using induced electromotive force (EMF) due to overshoot and the presence of multi-valued functions. Obtaining reliable and consistent inversion results using a uniform half-space as the initial model is challenging, especially when aiming for efficient inversion. Focusing on these problems, we use the land-based transient electromagnetic (TEM) sounding data, which was acquired by using a large fixed-loop transmitter, and adopt a quasi-2D inversion scheme to generate improved images of the subsurface resistivity structure. First, we have considered directly using magnetic field data or converting induced EMF into magnetic field, and then calculating the apparent resistivity over the whole zone. Next, a resistivity profile that varies with depth is obtained through fast smoke ring imaging. This profile serves as the initial model for the subsequent optimal inversion. The inversion scheme uses a nonlinear least-squares method, incorporating lateral and vertical constraints, to produce a quasi-2D subsurface image. The potentiality of the proposed methodology has been exemplified through the interpretation of synthetic data derived from a 3D intricate resistivity model, as well as field data obtained from a TEM survey conducted in a coalmine field. In both cases, the inversion process yields quasi-2D subsurface images that exhibit a reasonable level of accuracy. These images appear to be less moulded by 3D effects and demonstrate a satisfactory level of agreement with the known target area.
Improving medication adherence in glaucoma patients: a randomized controlled interventional study
Authors: Barakat Noor A , AlGhanem Rama , Abdulrazeq Bashar , AlKhatib Hatim S , AlRyalat Saif Aldeen , Muhsen Sana’ , AlMuhaissen Suha
Published: March 2024

Objectives

The main objective of our study was to assess the adherence of Jordanian patients to their glaucoma treatment after a brief educational session.

Methods

The current study was a randomized controlled interventional study. One hundred and ninety open-angle glaucoma patients were divided into control and intervention groups. After baseline assessment, patients in the intervention group received an educational session about glaucoma, while patients in the control group only received the usual care. Adherence to medication, eye drop administration technique, and knowledge about glaucoma were assessed at baseline and at follow-up.

Key findings

The mean MGL adherence scale score baseline value was 0.67 and significantly improved to 0.4 at the follow-up (P-value = .039) for patients in the intervention group. Multivariate regression showed that having less than three kids and experiencing glaucoma medication side effects were negatively correlated with adherence to glaucoma eye drops. The mean Eye Drops Administration scale score for patients in the intervention group improved significantly from 6.25 at baseline to 7.7 at the follow-up (P-value < .001). The mean knowledge scale score for the intervention group patients at baseline was 8.8, which significantly increased to 10 at the follow-up (P-value < .001). The knowledge score was found to be significantly higher for younger patients, those who have higher education levels and health care-related education, patients who rely on the ophthalmologist for glaucoma, and patients with a longer duration glaucoma.

Conclusions

A short educational session improves patients’ adherence, knowledge, and eye drop administration technique in the intervention group significantly. Patients in Jordan have a relatively high adherence to glaucoma medications. Educational sessions should be provided to glaucoma patients to help the patients in managing their condition.
Utility of Methicillin-Resistant Staphylococcus aureus Nasal PCR Testing in Pediatric Patients With Suspected Respiratory Infections
Authors: Baker Brooke , Hung Frances , Smith Michael J , Erkanli Alaattin , Greenhill Katherine , Hayes Jillian , Parish Alice , Zhou Grace , Moorthy Ganga S , Deri Connor R
Published: March 2024

Observational studies in adults suggest nasal methicillin-resistant Staphylococcus aureus (MRSA) swabs have a high negative predictive value (NPV) for ruling out MRSA pneumonia, however, pediatric data are limited. This retrospective study of 505 pediatric patients found a 99.8% NPV among children with suspected respiratory infections.
Presence of anti-RBC antibodies correlates with parasitaemia and once-infected RBCs but not the extent of post-malaria haemolysis
Authors: Tober-Lau Pinkus , Kneller Anna K , Lingscheid Tilman , Mayer Beate , Zoller Thomas , Kurth Florian
Published: March 2024

Highlights

In a cohort of patients treated with oral artemisinin combination therapy for uncomplicated malaria, the presence of anti-red blood cell (RBC) auto-antibodies does not correlate with the extent of post-treatment haemolysis. Patients with positive antibody screening test on d14 had higher initial parasitaemia and a higher number of once-infected RBCs throughout follow-up.
Drought decreases cotton fiber strength by altering sucrose flow route
Authors: Zhu Honghai , Hu Wei , Li Yuxia , Zou Jie , He Jiaqi , Wang Youhua , Meng Yali , Chen Binglin , Zhao Wenqing , Wang Shanshan , Zhou Zhiguo
Published: March 2024

The potential mechanisms by which drought restricts cotton fiber cell wall synthesis and fiber strength are still not fully understood. Herein, drought experiments were conducted using two cultivars of upland cotton (Gossypium hirsutum), Dexiamian 1 (drought-tolerant) and Yuzaomian 9110 (drought-sensitive). Results showed that drought notably reduced sucrose efflux from cottonseed coats to fibers by down-regulating the expression of GhSWEET10 and GhSWEET15 in outer cottonseed coats, leading to enhanced sucrose accumulation in cottonseed coats but decreased sucrose accumulation in fibers. Within cotton fibers, drought restricted the hydrolysis of sucrose to uridine-5ʹ-diphosphoglucose by suppressing sucrose synthase activity, and drought favored the conversion of uridine-5ʹ-diphosphoglucose to β-1,3-glucan rather than cellulose by up-regulating GhCALS5. Hence, cellulose content was reduced, which was the main reason for the decreased fiber strength under drought. Moreover, drought promoted lignin synthesis by up-regulating the expression of Gh4CL4, GhPAL9, GhCCR5, GhCAD11, and GhCOMT6, which partly offset the negative influence of reduced cellulose content on fiber strength. Compared with Yuzaomian 9110, the drought-tolerance of Dexiamian 1 was evidenced by the following under drought conditions: (i) greater sucrose flow from seedcoat to fiber, (ii) less β-1,3-glucan accumulation, and (iii) more lignin biosynthesis. Overall, this study provides new insights into the mechanism of reduced cotton fiber strength induced by drought.
Up-regulation of non-photochemical quenching improves water use efficiency and reduces whole-plant water consumption under drought in Nicotiana tabacum
Authors: Turc Benjamin , Sahay Seema , Haupt Jared , de Oliveira Santos Talles , Bai Geng , Glowacka Katarzyna
Published: March 2024

Water supply limitations will likely impose increasing restrictions on future crop production, underlining a need for crops that use less water per mass of yield. Water use efficiency (WUE) therefore becomes a key consideration in developing resilient and productive crops. In this study, we hypothesized that it is possible to improve WUE under drought conditions via modulation of chloroplast signals for stomatal opening by up-regulation of non-photochemical quenching (NPQ). Nicotiana tabacum plants with strong overexpression of the PsbS gene encoding PHOTOSYSTEM II SUBUNIT S, a key protein in NPQ, were grown under differing levels of drought. The PsbS-overexpressing lines lost 11% less water per unit CO2 fixed under drought and this did not have a significant effect on plant size. Depending on growth conditions, the PsbS-overexpressing lines consumed from 4–30% less water at the whole-plant level than the corresponding wild type. Leaf water and chlorophyll contents showed a positive relation with the level of NPQ. This study therefore provides proof of concept that up-regulation of NPQ can increase WUE, and as such is an important step towards future engineering of crops with improved performance under drought.
Cysteine post‐translational modifications regulate protein interactions of caveolin‐3
Authors: Ashford Fiona , Kuo Chien‐Wen , Dunning Emma , Brown Elaine , Calagan Sarah , Jayasinghe Izzy , Henderson Colin , Fuller William , Wypijewski Krzysztof
Published: March 2024

Caveolae are small flask‐shaped invaginations of the surface membrane which are proposed to recruit and co‐localize signaling molecules. The distinctive caveolar shape is achieved by the oligomeric structural protein caveolin, of which three isoforms exist. Aside from the finding that caveolin‐3 is specifically expressed in muscle, functional differences between the caveolin isoforms have not been rigorously investigated. Caveolin‐3 is relatively cysteine‐rich compared to caveolins 1 and 2, so we investigated its cysteine post‐translational modifications. We find that caveolin‐3 is palmitoylated at 6 cysteines and becomes glutathiolated following redox stress. We map the caveolin‐3 palmitoylation sites to a cluster of cysteines in its C terminal membrane domain, and the glutathiolation site to an N terminal cysteine close to the region of caveolin‐3 proposed to engage in protein interactions. Glutathiolation abolishes caveolin‐3 interaction with heterotrimeric G protein alpha subunits. Our results indicate that a caveolin‐3 oligomer contains up to 66 palmitates, compared to up to 33 for caveolin‐1. The additional palmitoylation sites in caveolin‐3 therefore provide a mechanistic basis by which caveolae in smooth and striated muscle can possess unique phospholipid and protein cargoes. These unique adaptations of the muscle‐specific caveolin isoform have important implications for caveolar assembly and signaling.
Long-term Survival after Volatile or Propofol General Anesthesia for Bladder Cancer Surgery: A Retrospective National Registry Cohort Study
Authors: Enlund Mats , Hållberg Hampus , Berglund Anders , Sherif Amir , Enlund Anna , Bergkvist Leif
Published: March 2024

Background

Prospective interventional trials and retrospective observational analyses provide conflicting evidence regarding the relationship between propofol versus inhaled volatile general anesthesia and long-term survival after cancer surgery. Specifically, bladder cancer surgery lacks prospective clinical trial evidence.

Methods

Data on bladder cancer surgery performed under general anesthesia between 2014 and 2021 from the National Quality Registry for Urinary Tract and Bladder Cancer and the Swedish Perioperative Registry were record-linked. Overall survival was compared between patients receiving propofol or inhaled volatile for anesthesia maintenance. The minimum clinically important difference was defined as a 5–percentage point difference in 5-yr survival.

Results

Of 7,571 subjects, 4,519 (59.7%) received an inhaled volatile anesthetic, and 3,052 (40.3%) received propofol for general anesthesia maintenance. The two groups were quite similar in most respects but differed in American Society of Anesthesiologists Physical Status and tumor stage. Propensity score matching was used to address treatment bias. Survival did not differ during follow-up (median, 45 months [interquartile range, 33 to 62 months]) in the full unmatched cohort nor after 1:1 propensity score matching (3,052 matched pairs). The Kaplan–Meier adjusted 5-yr survival rates in the matched cohort were 898 of 3,052, 67.5% (65.6 to 69.3%) for propofol and 852 of 3,052, 68.5% (66.7 to 70.4%) for inhaled volatile general anesthesia, respectively (hazard ratio, 1.05 [95% CI, 0.96 to 1.15]; P = 0.332). A sensitivity analysis restricted to 1,766 propensity score–matched pairs of patients who received only one general anesthetic during the study period did not demonstrate a difference in survival; Kaplan–Meier adjusted 5-yr survival rates were 521 of 1,766, 67.1% (64.7 to 69.7%) and 482 of 1,766, 68.9% (66.5 to 71.4%) for propofol and inhaled volatile general anesthesia, respectively (hazard ratio, 1.09 [95% CI, 0.97 to 1.23]; P = 0.139).

Conclusions

Among patients undergoing bladder cancer surgery under general anesthesia, there was no statistically significant difference in long-term overall survival associated with the choice of propofol or an inhaled volatile maintenance.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
Alternate Electrode Placements to Facilitate Frontal Electroencephalography Monitoring in Anesthetized and Critically Ill Patients
Authors: Isik Oliver G. , Chauhan Vikas , Ahmed Meah T. , Chang Brian A. , Cassim Tuan Z. , Graves Morgan C. , Rajan Shobana , Garcia Paul S.
Published: March 2024

Background:

Frontal electroencephalography (EEG) monitoring can be useful in guiding the titration of anesthetics, but it is not always feasible to place electrodes in the standard configuration in some circumstances, including during neurosurgery. This study compares 5 alternate configurations of the Masimo Sedline Sensor.

Methods:

Ten stably sedated patients in the intensive care unit were recruited. Frontal EEG was monitored in the standard configuration (bifrontal upright) and 5 alternate configurations: bifrontal inverse, infraorbital, lateral upright, lateral inverse, and semilateral. Average power spectral densities (PSDs) with 95% CIs in the alternate configurations were compared to PSDs in the standard configuration. Two-one-sided-testing with Wilcoxon signed-rank tests assessed equivalence in the spectral edge frequency (SEF-95), EEG power, and relative delta (0.5 to 3.5 Hz), alpha (8 to 12 Hz), and beta (20 to 30 Hz) power between each alternate and standard configurations.

Results:

After the removal of unanalyzable tracings, 7 patients were included for analysis in the infraorbital configuration and 9 in all other configurations. In the lateral upright and lateral inverse configurations, PSDs significantly differed from the standard configuration within the 15 to 20 Hz band. The greatest decrease in EEG power was in the lateral inverse configuration (median: −97 dB; IQR: −130, −62 dB). The largest change in frequency distribution of EEG power was in the infraorbital configuration; median SEF-95 change of −1.4 Hz (IQR: −2.8, 0.7 Hz), median relative delta power change of +7.3% (IQR: 1.4%, 7.9%), and median relative alpha power change of −0.6% (IQR: −5.7%, 0.0%).

Conclusions:

These 5 alternate Sedline electrode configurations are suitable options for monitoring frontal EEG when the standard configuration is not possible.
Location, location, location: How does residency program leadership vary according to geographic region?
Authors: Huyke-Hernández Fernando A. , Doxey Stephen A. , Qian Lily J. , Heare Austin , Cunningham Brian P.
Published: March 2024

Background:

Faculty relationships are key to resident education. Residency applicants may find it more appealing to choose programs where the faculty have a similar background. With the addition of geographic preferences to the application process, applicants may find it beneficial to know general faculty makeup in each region. The purpose of this study was to evaluate the relationship of geographic location and orthopaedic residency leadership characteristics.

Methods:

The Accreditation Council for Graduate Medical Education (ACGME) and Doximity websites were queried in September 2022 to identify United States orthopaedic residency programs for the 2022-2023 cycle. Program attributes were categorized by region. Program leaders evaluated in this study consisted of Chairs, Vice Chairs, Program Directors (PDs), and Assistant PDs.

Results:

A total of 192 programs with 425 leaders were included. Leaders were mostly PDs (42.6%, n=181), men (88.7%, n=377), MDs (90.6%, n=385), and trained in the US (96.9%, n=412). The Northeast had the most programs (n=59, 30.7%) and leadership positions (n=136, 32.0%). The West had higher proportions of internationally-trained and women leaders (8.2%, P=0.046 and 18.0%, P=0.072), although the latter only trended towards significance. The South contained the lowest prevalence of internationally-trained leaders (0.8%, P=0.046). The Midwest exhibited the largest amount of DO leadership (16.0%, P=0.022). The Northeast had more surgeons subspecialized in hand/upper extremity (19.9% vs. 10.0%, P=0.033) yet relatively fewer in oncology (2.9% vs. 10.7%, P=0.041).

Conclusions:

Program attributes varied by region. This information is valuable to applicants and leaders as the field strives to strengthen and diversify its leadership.
Precision dosing for patients on tricyclic antidepressants
Authors: Nakad Zahi , Saab Yolande
Published: March 2024

Objective

We aim to develop a personalized dosing tool for tricyclic antidepressants (TCAs) that integrates CYP2D6 and CYP2C19 gene variants and their effects while also considering the polypharmacy effect.

Methods

The study first adopted a scoring system that assigns weights to each genetic variant. A formula was then developed to compute the effect of both genes’ variants on drug dosing. The output of the formula was assessed by a comparison with the clinical pharmacogenetics implementation consortium recommendation. The study also accounts for the effect of the co-administration of inhibitors and inducers on drug metabolism. Accordingly, a user-friendly tool, Clinical Dosing Tool ver.2, was created to assist clinicians in dosing patients on TCAs.

Results

The study provides a comprehensive list of all alleles with corresponding activity values and phenotypes for both enzymes. The tool calculated an updated area under the curve ratio that utilizes the effects of both enzymes’ variants for dose adjustment. The tool provided a more accurate individualized dosing that also integrates the polypharmacy effect.

Conclusion

To the best of our knowledge, the literature misses such a tool that provides a numerical adjusted dose based on continuous numerical activity scores for the considered patients’ alleles and phenoconversion.
Associations of ADH1B and ALDH2 genotypes and alcohol flushing with drinking history, withdrawal symptoms, and ICD-10 criteria in Japanese alcohol-dependent men
Authors: Yokoyama Akira , Yokoyama Tetsuji , Yumoto Yosuke , Takimura Tsuyoshi , Toyama Tomomi , Yoneda Junichi , Nishimura Kotaro , Minobe Ruriko , Matsuzaki Takanobu , Kimura Mitsuru , Matsushita Sachio
Published: March 2024

Objectives

Given the high prevalence of fast-metabolizing alcohol dehydrogenase-1B*2 (ADH1B*2) and inactive aldehyde dehydrogenase-2*2 (ALDH2*2) alleles in East Asians, we evaluated how the ADH1B/ALDH2 genotypes and alcohol flushing might affect the development of alcohol dependence (AD).

Methods

We evaluated how the ADH1B/ALDH2 genotypes and self-reported alcohol flushing affected history of drinking events and withdrawal symptoms and ICD-10 criteria in 4116 Japanese AD men.

Results

The ADH1B*1/*1 group and ALDH2*1/*1 group were 1–5 years younger than the ADH1B*2(+) and ALDH2*1/*2 groups, respectively, for all of the ages at onset of habitual drinking, blackouts, daytime drinking, uncontrolled drinking, withdrawal symptoms, and first treatment for AD, and the current age. Blackouts were more common in the ADH1B*1/*1 group and ALDH2*1/*1 group. Daytime drinking, uncontrolled drinking, and withdrawal symptoms, such as hand tremor, sweating, convulsions, and delirium tremens/hallucinations were more common in the ADH1B*1/*1 group. The ADH1B*1/*1 was positively associated with the ICD-10 criteria for ‘tolerance’ and ‘withdrawal symptoms’. The ADH1B*1/*1 group and ALDH2*1/*2 group had a larger ICD-10 score. Never flushing was reported by 91.7% and 35.2% of the ALDH2*1/*1 and ALDH2*1/*2 carriers, respectively. After a 1–2-year delay in the onset of habitual drinking in the former-/current-flushing group, no differences in the ages of the aforementioned drinking milestones were found according to the flushing status.

Conclusion

The ADH1B*1/*1 and ALDH2*1/*1 accelerated the development of drinking events and withdrawal symptoms in Japanese AD patients. ICD-10 score was larger in the ADH1B*1/*1 group and ALDH2*1/*2 group. The effects of alcohol flushing on drinking events were limited.
Inhibition of sodium-glucose cotransporter-2 and liver-related complications in individuals with diabetes: a Mendelian randomization and population-based cohort study
Authors: Chung Sung Won , Moon Hye-Sung , Shin Hyunjae , Han Hyein , Park Sehoon , Cho Heejin , Park Jeayeon , Hur Moon Haeng , Park Min Kyung , Won Sung-Ho , Lee Yun Bin , Cho Eun Ju , Yu Su Jong , Kim Dong Ki , Yoon Jung-Hwan , Lee Jeong-Hoon , Kim Yoon Jun
Published: March 2024

Background and Aims:

No medication has been found to reduce liver-related events. We evaluated the effect of sodium-glucose cotransporter-2 inhibitor (SGLT2i) on liver-related outcomes.

Approach and Results:

Single nucleotide polymorphisms associated with SGLT2 inhibition were identified, and a genetic risk score (GRS) was computed using the UK Biobank data (n=337,138). Two-sample Mendelian randomization (MR) was conducted using the FinnGen (n=218,792) database and the UK Biobank data. In parallel, a nationwide population-based study using the Korean National Health Insurance Service (NHIS) database was conducted. The development of liver-related complications (ie, hepatic decompensation, HCC, liver transplantation, and death) was compared between individuals with type 2 diabetes mellitus and steatotic liver diseases treated with SGLT2i (n=13,208) and propensity score–matched individuals treated with dipeptidyl peptidase-4 inhibitor (n=70,342). After computing GRS with 6 single nucleotide polymorphisms (rs4488457, rs80577326, rs11865835, rs9930811, rs34497199, and rs35445454), GRS-based MR showed that SGLT2 inhibition (per 1 SD increase of GRS, 0.1% lowering of HbA1c) was negatively associated with cirrhosis development (adjusted odds ratio=0.83, 95% CI=0.70–0.98, p=0.03) and this was consistent in the 2-sample MR (OR=0.73, 95% CI=0.60–0.90, p=0.003). In the Korean NHIS database, the risk of liver-related complications was significantly lower in the SGLT2i group than in the dipeptidyl peptidase-4 inhibitor group (adjusted hazard ratio=0.88, 95% CI=0.79–0.97, p=0.01), and this difference remained significant (adjusted hazard ratio=0.72–0.89, all p<0.05) across various sensitivity analyses.

Conclusions:

Both MRs using 2 European cohorts and a Korean nationwide population-based cohort study suggest that SGLT2 inhibition is associated with a lower risk of liver-related events.
Cognitive Behavioral Therapy for Insomnia Improves Sleep Outcomes in Individuals With Concussion: A Preliminary Randomized Wait-List Control Study
Authors: Ludwig Rebecca , Rippee Michael , D’Silva Linda , Radel Jeff , Eakman Aaron M. , Beltramo Alvin , Drerup Michelle , Siengsukon Catherine
Published: March 2024

Objective:

Cognitive behavioral therapy for insomnia (CBT-I) is the gold standard treatment for insomnia, but there is limited evidence on the treatment effect of CBT-I in individuals after a concussion. Therefore, the main purpose of this study was to evaluate the treatment effect of CBT-I on sleep outcomes and postconcussion symptoms.

Setting:

This study was conducted at an academic institution. The CBT-I sessions were conducted using a teleconferencing system (Zoom).

Participants:

Participants were eligible to participate if they were at least 4 weeks post- concussion, aged 18 to 64 years, and scored 10 or more on the Insomnia Severity Index. A total of 40 people were enrolled; 32 participants were included in analyses.

Design:

This was a randomized controlled wait-list study. Participants were randomized into starting the CBT-I intervention immediately after the baseline assessment or into the wait-list group for 6 weeks before starting CBT-I. Assessments were performed at baseline, 6, 12, and 18 weeks.

Main Measures:

The primary outcome was the Insomnia Severity Index. Secondary measures included the Pittsburg Sleep Quality Index, Post-Concussion Symptom Scale, and Beck Depression and Anxiety Inventories. Statistical analyses included a repeated-measures analysis of variance, t tests, and mixed linear regression modeling.

Results:

There was a group-by-time interaction for the sleep outcomes but not for the concussion or mood outcomes. Differences were seen between groups on sleep outcomes, symptom severity, and depression. The treatment effect was maintained following CBT-I for all outcomes. Improvement in sleep outcomes was predictive of improvement in postconcussion symptom severity and number of symptoms.

Conclusions:

CBT-I reduces insomnia in individuals with concussions, and improved sleep was associated with lower postconcussion and mood symptoms. These effects were maintained 6 to 12 weeks following the intervention.
Systemic medications for sickle cell disease and potential applications for sickle cell retinopathy
Authors: Garg Anupam K. , Scott Adrienne W.
Published: March 2024

Purpose of review

To review the literature evaluating systemic medications for treatment of sickle cell disease (SCD) and their applications for sickle cell retinopathy.

Recent Findings

Prior studies have demonstrated the efficacy of traditional systemic therapies in reducing the risk of development of sickle cell retinopathy. Since 2017, several new and promising disease-modifying therapies for sickle cell disease have been approved for clinical use, including the first genetic therapies such as exagamglogene autotemcel (exa-cel) and lovotibeglogene autotemcel (lovo-cel). These treatments have shown promising results for systemic management but are not widely utilized due to limited access and high cost. The efficacy of these therapies for the prevention of sickle cell retinopathy remains unknown and opens the door to new avenues for research. Furthermore, the role of systemic therapy for the management of hemoglobin SC (HbSC) disease, which has milder systemic effects but higher likelihood of causing retinopathy, remains poorly understood.

Hydroxyurea has been a mainstay of systemic management of SCD with prior work suggesting its ability to reduce the likelihood of developing retinopathy. There are several new and potentially curative systemic therapies for SCD, though their role in retinopathy prevention and management has not been studied extensively. Future studies are necessary to understand the implications of these emerging therapies for sickle cell retinopathy.
Seeking Validation and Creating Meaningful Interactions
Authors: Pfeiffer Danika L. , Hess Christine Reiner , Landa Rebecca J.
Published: March 2024

Infancy, a formative period for development, has been identified as an advantageous time to provide family-centered support for children with delays. Families should be included as stakeholders during development of such interventions to ensure social value. We describe a preliminary randomized controlled trial evaluating Infant Achievements (IA), an 8-week (16-session) parent-mediated intervention for parents of infants 8–12 months old with social and communication delays. This study reports our qualitative examination of the intervention's social validity. We conducted focus groups with seven IA parent participants and analyzed their responses using conventional content analysis. Five themes emerged: (a) difficulty identifying resources to address concerns; (b) seeking validation of concerns; (c) seeking support to enhance children's development; (d) experiencing a supportive coaching relationship; and (e) creating meaningful interactions to support children's communication and social skills. Our results emphasize the necessity of partnering with families in the development of evidence-based, family-centered interventions for infants with developmental delays to maximize their social value.
Peripheral defocus of monofocal intraocular lenses
Authors: Natarajan Ramya , Maceo Heilman Bianca , Ho Arthur , Singh Vivek M. , Ruggeri Marco , Mohamed Ashik , Reddy Jagadesh C. , Parel Jean-Marie A. , Vadavalli Pravin K. , Manns Fabrice
Published: March 2024

Purpose:

To quantify the angular dependence of monofocal intraocular lens (IOL) power.

Setting:

Ophthalmic Biophysics Laboratory, Kallam Anji Reddy campus, L V Prasad Eye Institute, Hyderabad, India.

Design:

Laboratory study.

Methods:

Experiments were performed on IOLs from 2 different manufacturers (APPALENS 207, Appasamy Associates and SN60WF, Alcon Laboratories, Inc.). IOL powers ranged from 17 to 25 diopters (D). The IOLs were mounted in a fluid-filled chamber, and the on-axis and off-axis powers were measured using a laser ray tracing system over the central 3 mm zone with delivery angles ranging from −30 to +30 degrees in 5-degree increments. The position of the best focus was calculated for each IOL at each angle. The angular dependence of IOL power was compared with theoretical predictions.

Results:

Peripheral defocus increased significantly with increasing incidence angle and power. The peripheral defocus at ±30 degrees increased from 5.8 to 8.5 D when the power increased from 17.5 to 24.5 D for APPALENS 207 and from 4.9 to 7.4 D when the power increased from 17 to 25 D for SN60WF. The mean difference between the measured and theoretical tangential power at ±30 degrees was 0.50 ± 0.16 D for the APPALENS 207 and −0.40 ± 0.10 D for the SN60WF, independent of IOL power.

Conclusions:

IOLs introduce a significant amount of peripheral defocus which varies significantly with IOL power and design. Given that peripheral defocus is related to lens power, replacement of the crystalline lens (approximately 24 D) with an IOL will produce a significant difference in peripheral defocus profile after surgery.
Randomized clinical trial comparing customized corneal crosslinking: epi-on in high oxygen and epi-off in room air for keratoconus
Authors: Elving Sofie , Fredriksson Anneli , Beckman Rehnman Jeannette , Behndig Anders
Published: March 2024

Purpose:

To compare clinical outcomes of customized transepithelial (epi-on) corneal crosslinking (CXL) in high oxygen and customized CXL with epithelial removal (epi-off) in room air for keratoconus (KC).

Setting:

Umeå University Hospital, Umeå, Sweden.

Design:

Prospective, randomized, single-masked, intraindividually comparing study.

Methods:

32 participants with bilateral progressive KC were treated with bilateral customized topography-guided CXL, 30 mW/cm2; 7.2 to 15 J/cm2 and were randomized to epi-on in one eye (32 eyes) and epi-off in the fellow eye (32 eyes). Uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA), maximal keratometry (Kmax), subjective ocular discomfort, low-contrast visual acuities (LCVAs) at 10% and 2.5% contrast, ocular and anterior corneal wavefront aberrations, manifest refractive spherical equivalent, endothelial cell count (ECC), and adverse events were assessed through 24 months.

Results:

Both treatments showed improvements at 24 months in UDVA; −0.16 ± 0.24 (P < .001) and −0.13 ± 0.20 logMAR (P = .006), respectively, CDVA; −0.10 ± 0.11 (P < .001) and −0.10 ± 0.12 (P = .001), Kmax; −1.74 ± 1.31 (P < .001) and −1.72 ± 1.36 D (P < .001). LCVA 10% improved for both protocols (P < .001), but LCVA 2.5% improved for epi-on CXL only (P = .001). ECC was unaltered, and no adverse events occurred. The epi-on eyes had significantly less discomfort symptoms during the whole first week posttreatment (P < .05).

Conclusions:

High-oxygen customized epi-on CXL is a viable alternative to room air customized epi-off CXL, with faster improvements in CDVA and LCVA and less early ocular discomfort.
Patient Engagement Functionalities’ Influence on Quality Outcomes: The Road via EHR Presence
Authors: Upadhyay Soumya , Bhandari Neeraj
Published: March 2024

Goal:

Patients engaged in self-care through information technology can potentially improve the quality of healthcare they receive. This study aimed to examine how electronic health record (EHR) system functionalities help hospitals mediate the impact of patient engagement on quality outcomes—notably, readmission rates.

Methods:

A pooled cross-sectional study design employed data containing 3,547 observations from general acute care hospitals (2014–2018). The breadth of patient engagement functionalities adopted by a hospital was used as the independent variable and the degree of EHR presence was used as the mediating variable. Mean time to readmission for acute myocardial infarction (AMI), pneumonia, and heart failure were the dependent variables. The Baron and Kenny method was used to test mediation.

Principal Findings:

Patient engagement was associated with reduced AMI readmission rates both directly and via EHR system presence. Mediation effects were present, in that a 1-unit increase in patient engagement through EHR system presence was associated with a 0.33% decrease in AMI readmission rates (p < .05). For other disease categories (heart failure and pneumonia), a significant effect was not found.

Practical Applications:

For hospitals with a comprehensive EHR system, patient engagement through information technology can potentially reduce readmission rates for some diseases. More research is needed to determine which specific clinical conditions are amenable to quality improvement through patient engagement. Synergies between patient engagement functionalities and an EHR system positively affect quality outcomes. Therefore, practitioners and hospital managers should leverage hospital investments made in their EHR system infrastructure and use it to engage patients in self-care.
Performance of Different Follow-Up Strategies and Genotype-Based Recurrence Risk After Treatment of Cervical High-Grade Squamous Intraepithelial Lesion
Authors: Graça Joana , Preti Mario , Pollano Benedetta , Vieira-Baptista Pedro
Published: March 2024

Objective

Our aim was to evaluate the performance of different follow-up strategies after treatment for cervical intraepithelial neoplasia (CIN) 2 or 3, including human papillomavirus (HPV) detection, cytology, or colposcopy, as well as their combinations. Additionally, we compared the influence of the persistence of HPV 16/18 versus that of other high-risk HPV genotypes (HR-HPV) in the recurrence risk.

Methods

Retrospective register-based study, including women who had an excision of the transformation zone for CIN2 or CIN3 at our institution, between January 2011 and December 2022. The outcome assessed was histopathological recurrence/persistence of CIN2 or worse.

Results

Of the 721 women included, 6.8% (49/721) had recurrence/persistence. The sensitivity, specificity, and positive and negative predictive values of the HPV test were 97.4%, 80%, 22.3%, and 99.8%, respectively, whereas for cotesting (HR-HPV and cytology), 86.8%, 90.1%, 34.4%, and 99.1%, respectively. The referral rates for colposcopy were 24.3% and 14.2%, respectively. The sensitivity of colposcopy was low (40.0%).

Women who were initially positive for non-16/18 genotypes at baseline who became HPV16/18 positive during follow-up, had a statistically significant increased risk of CIN2 or worse, compared with those who tested positive only for other HR-HPV genotypes during both stages (hazard ratio = 4.98; 95% CI = 1.66–14.91).

Conclusions

Human papillomavirus testing is the best strategy for follow-up after treatment of cervical HSIL. The addition of cytology triage decreases by more than 40% the referrals for colposcopy, without significantly missing cases of recurrence/persistence. Human papillomavirus 16/18 in the follow-up, regardless of being previously positive, is associated with higher risk of recurrence/persistence of HSIL.