bluuebunny/crossref_metadata_2025 huggingface dataset:
Operative vs Nonoperative Management of Unstable Medial Malleolus Fractures
Authors: Carter Thomas H. , Oliver William M. , Bell Katrina R. , Graham Catriona , Duckworth Andrew D. , White Timothy O.
Published: January 2024

Importance

Unstable ankle fractures are routinely managed operatively. However, because of soft tissue and implant-related complications, recent literature has reported on the nonoperative management of well-reduced medial malleolus fractures after fibular stabilization, but with limited evidence supporting the routine application.

Objective

To assess the superiority of internal fixation of well-reduced (displacement ≤2 mm) medial malleolus fractures compared with nonfixation after fibular stabilization.

Design, Setting, and Participants

This superiority, pragmatic, parallel, prospective randomized clinical trial was conducted from October 1, 2017, to August 31, 2021. A total of 154 adult participants (≥16 years) with a closed, unstable bimalleolar or trimalleolar ankle fracture requiring surgery at an academic major trauma center in the UK were assessed. Exclusion criteria included injuries with no medial-sided fracture, open fractures, neurovascular injury, and the inability to comply with follow-up. Data analysis was performed in July 2022 and confirmed in September 2023.

Interventions

Once the lateral (and where appropriate, posterior) malleolus had been fixed and satisfactory intraoperative reduction of the medial malleolus fracture was confirmed by the operating surgeon, participants were randomly allocated to fixation (n = 78) or nonfixation (n = 76) of the medial malleolus.

Main Outcome and Measure

Olerud-Molander Ankle Score (OMAS) 1 year after randomization (range, 0-100 points, with 0 indicating worst possible outcome and 100 indicating best possible outcome).

Results

Among 154 randomized participants (mean [SD] age, 56.5 [16.7] years; 119 [77%] female), 144 (94%) completed the trial. At 1 year, the median OMAS was 80.0 (IQR, 60.0-90.0) in the fixation group compared with 72.5 (IQR, 55.0-90.0) in the nonfixation group (P = .17). Complication rates were comparable. Significantly more patients in the nonfixation group developed a radiographic nonunion (20% vs 0%; P < .001), with 8 of 13 clinically asymptomatic; 1 patient required surgical reintervention for this. Fracture type and reduction quality appeared to influence fracture union and patient outcome.

Conclusions and Relevance

In this randomized clinical trial comparing internal fixation of well-reduced medial malleolus fractures with nonfixation, after fibular stabilization, fixation was not superior according to the primary outcome. However, 1 in 5 patients developed a radiographic nonunion after nonfixation, and although the reintervention rate to manage this was low, the future implications are unknown. These results support selective nonfixation of anatomically reduced medial malleolar fractures after fibular stabilization.

Trial Registration

ClinicalTrials.gov Identifier: NCT03362229
Intra-Anterior Chamber Injection of Ranibizumab in Advanced Pediatric Vitreoretinal Diseases
Authors: Zhang Wenting , Liu Huanyu , Chen Yiye , Zhang Xuerui , Gu Victoria Y. , Xiao Haodong , Yang Yuan , Yin Jiawei , Peng Jie , Zhao Peiquan
Published: January 2024

Importance

Anti–vascular endothelial growth factor (VEGF) treatment through intravitreal or subretinal administrations has been proven effective for VEGF-driven pediatric vitreoretinal diseases but are not feasible for advanced cases, such as shallow traction retinal detachments or peripheral circumferential retinal detachments which adhere to the lens. Intra-anterior chamber injection (IAcI) of anti-VEGF may be a viable alternative in such cases but needs evaluation.

Objective

To investigate the effects and safety of IAcI of anti-VEGF to treat VEGF-driven pediatric vitreoretinal diseases.

Design, Setting, and Participants

This was a retrospective observational case series study conducted at Xinhua Hospital, affiliated with Shanghai Jiao Tong University School of Medicine in China. The study included 14 eyes of 13 children diagnosed with vitreoretinal disease exhibiting elevated vascular activity between January and August 2023.

Intervention

IAcI with ranibizumab.

Main Outcomes and Measures

Retinal vascular abnormalities, vitreous hemorrhage resolution, and complications 1 month and 3 months after injection.

Results

Of 13 patients included in this study, 12 were male. The mean age was 4.6 years (range, 1 month to 9 years). Six patients were diagnosed with familial exudative vitreoretinopathy, 4 with morning glory syndrome, 1 with retinopathy of prematurity, and 2 with chronic retinal detachments of unknown causes. At 1-month postoperative follow-up, vascular activity had decreased in 14 of 14 eyes. At 3-month follow-up, vascular activity had resolved in 7 of 14 eyes, persisted in 6 of 14 eyes, and reactivated in 1 of 14 eyes. On final observation, no complications were reported.

Conclusions and Relevance

These findings support the possibility of treatment using IAcI with ranibizumab to decrease retinal vascular abnormalities in familial exudative vitreoretinopathy or retinopathy of prematurity or related conditions, but further studies are needed to understand more precise benefits and risks. This approach might be considered in cases where intravitreal or subretinal injection are not feasible, recognizing the limitations of these findings and that longer-term outcomes still need to be monitored.
Olfaction and Mobility in Older Adults
Authors: Yuan Yaqun , Chamberlin Keran W. , Li Chenxi , Luo Zhehui , Simonsick Eleanor M. , Kucharska-Newton Anna , Chen Honglei
Published: January 2024

Importance

Decreased mobility is a hallmark of aging. Olfactory dysfunction is common in older adults and may be associated with declines in mobility.

Objective

To determine whether poor olfaction was associated with faster declines in mobility in older adults.

Design, Setting, and Participants

This cohort study included 2500 participants from the Health, Aging, and Body Composition Study. Participants completed the Brief Smell Identification Test during the year 3 clinical visit (1999-2000) and were followed for up to 7 years. A data analysis was conducted between January and July 2023.

Exposures

Olfaction was defined as good (test score, 11-12), moderate (9-10), hyposmia (7-8), or anosmia (0-6).

Main Outcomes and Measures

Mobility was measured using the 20-m usual and fast walking tests in clinical visit years 3 to 6, 8, and 10 and the 400-m fast walking test in years 4, 6, 8, and 10.

Results

The primary analyses included 2500 participants (1292 women [51.7%]; 1208 men [48.3%]; 960 Black [38.4%] and 1540 White [61.6%] individuals; mean [SD] age, 75.6 [2.8] years). Multivariate-adjusted analyses showed that poor olfaction was associated with slower walking speed at baseline and a faster decline over time. Taking the 20-m usual walking test as an example, compared with participants with good olfaction, the speed at baseline was 0.027 (95% CI, 0-0.053) m/s slower for those with hyposmia and 0.034 (95% CI, 0.005-0.062) m/s slower for those with anosmia. Longitudinally, the annual decline was 0.004 (95% CI, 0.002-0.007) m/s/year faster for those with hyposmia and 0.01 (95% CI, 0.007-0.013) m/s/year faster for those with anosmia. Similar results were obtained for the 20-m and 400-m fast walking tests. Further, compared with participants with good olfaction, the odds of being unable to do the 400-m test were 2.02 (95% CI, 1.17-3.48) times higher for those with anosmia at the year 8 visit and 2.73 (95% CI, 1.40-5.35) times higher at year 10. Multiple sensitivity and subgroup analyses supported the robustness and generalizability of the findings.

Conclusion and Relevance

The results of this cohort study suggest that poor olfaction is associated with a faster decline in mobility in older adults. Future studies should investigate underlying mechanisms and potential health implications.
Sorting lung tumor volumes from 4D‐MRI data using an automatic tumor‐based signal reduces stitching artifacts
Authors: Warren Mark , Barrett Alexander , Bhalla Neeraj , Brada Michael , Chuter Robert , Cobben David , Eccles Cynthia L. , Hart Clare , Ibrahim Ehab , McClelland Jamie , Rea Marc , Turtle Louise , Fenwick John D.
Published: January 2024

Purpose

To investigate whether a novel signal derived from tumor motion allows more precise sorting of 4D‐magnetic resonance (4D‐MR) image data than do signals based on normal anatomy, reducing levels of stitching artifacts within sorted lung tumor volumes.

Methods

(4D‐MRI) scans were collected for 10 lung cancer patients using a 2D T2‐weighted single‐shot turbo spin echo sequence, obtaining 25 repeat frames per image slice. For each slice, a tumor‐motion signal was generated using the first principal component of movement in the tumor neighborhood (TumorPC1). Signals were also generated from displacements of the diaphragm (DIA) and upper and lower chest wall (UCW/LCW) and from slice body area changes (BA). Pearson r coefficients of correlations between observed tumor movement and respiratory signals were determined. TumorPC1, DIA, and UCW signals were used to compile image stacks showing each patient's tumor volume in a respiratory phase. Unsorted image stacks were also built for comparison.

For each image stack, the presence of stitching artifacts was assessed by measuring the roughness of the compiled tumor surface according to a roughness metric (Rg). Statistical differences in weighted means of Rg between any two signals were determined using an exact permutation test.

Results

The TumorPC1 signal was most strongly correlated with superior‐inferior tumor motion, and had significantly higher Pearson r values (median 0.86) than those determined for correlations of UCW, LCW, and BA with superior‐inferior tumor motion (p < 0.05).

Weighted means of ratios of Rg values in TumorPC1 image stacks to those in unsorted, UCW, and DIA stacks were 0.67, 0.69, and 0.71, all significantly favoring TumorPC1 (p = 0.02–0.05). For other pairs of signals, weighted mean ratios did not differ significantly from one.

Conclusion

Tumor volumes were smoother in 3D image stacks compiled using the first principal component of tumor motion than in stacks compiled with signals based on normal anatomy.
Peripheral nervous system manifestations of MOG antibody associated disease
Authors: Gupta Pranjal , Paul Pritikanta , Redenbaugh Vyanka , Guo Yong , Lucchinetti Claudia , Abdulrahman Yahya , Datta Abhigyan , Shah Shailee , Klein Christopher J. , Pittock Sean J. , Flanagan Eoin P. , Dubey Divyanshu
Published: January 2024

Recent studies have reported the involvement of peripheral nervous system (PNS) in association with MOG‐IgG, including isolated neuropathies. In this retrospective study we characterized the PNS involvement in MOG antibody associated disease (MOGAD). Six out of 215 MOGAD patients had PNS involvement (all polyradiculopathy) that occurred concurrently with a CNS demyelinating episode. We also demonstrated MOG expression in healthy human controls' proximal nerve root. Nine patients with true‐positive MOG‐IgG1 had PNS involvement temporally unrelated to a CNS demyelinating event. All these patients had an alternate etiology of PNS involvement. Isolated peripheral neuropathy is not a feature of MOGAD, but inflammatory nerve root involvement can occur concurrently with CNS demyelinating events.
Restrained Li|Garnet Interface Contact Deterioration Manipulated by Lithium Modification for Solid‐State Batteries
Authors: Zhu Fangjun , Hu Xinyu , Xu Laiqiang , Zhang Baichao , Wang Haoji , Ni Lianshan , Deng Weina , Deng Wentao , Zou Guoqiang , Hou Hongshuai , Ji Xiaobo
Published: January 2024

Garnet solid state electrolytes (SSEs) have emerged as propitious candidates for solid‐state batteries (SSBs) with exceptional ionic conductivity and excellent (electro)chemical stability. However, the Li|garnet interface contact deterioration still remains a major challenge resulting in Li dendrite propagation. Herein, a method is proposed to strengthen the adhesion of garnet SSE and Li by incorporating Sr3N2 into the Li metal. Density functional theory (DFT) calculations reveal that the interfacial formation energy of Li|garnet is decreased by the obtained Li‐Sr‐N (LSN) composite, which can enable a shift from poor contact to intimate bonding at the Li|garnet interface and a homogenous Li+ flux as well as electric field distribution. Simultaneously, the produced Li3N and LiSrN, which are known for their strong Li adsorption affinity and rapid Li+ transfer kinetics, actively govern the Li plating process. Thereby this rational design brings a notable reduction in interfacial impedance (4.5 Ω cm2), along with the increased critical current density (1.3 mA cm−2) and enhanced cycle stability (1200 h at 0.3 mA cm−2). Furthermore, The LFP|garnet|LSN full cell has demonstrated remarkable cycling performance (95.9% capacity retention after 200 cycles at 1 C) and favorable rate capability (150.2 mAh g−1 at 0.1 C and 134.9 mAh g−1 at 1 C). The research provides a new sight into lithium modification that can restrain Li|garnet interface deterioration and lay the groundwork for future advancements in high‐performance garnet‐ based SSBs.
Cognitive change in prevalent and incident hearing loss: The Maastricht Aging Study
Authors: Soons Lion M. , Deckers Kay , Tange Huibert , van Boxtel Martin P. J. , Köhler Sebastian
Published: January 2024

INTRODUCTION

Hearing loss (HL) has been associated with cognitive decline and dementia. We examined the temporal association between prevalent and incident HL and cognitive change.

METHODS

A total of 1823 participants (24‐82 years) from the Maastricht Aging Study (MAAS) were assessed at baseline, 6 and 12 years, including pure‐tone audiometry. Linear‐mixed models were used to test the association between HL and cognition, adjusted for demographics and other dementia risk factors.

RESULTS

Participants with prevalent and incident HL showed a faster decline in verbal memory, information processing speed, and executive function than participants without HL. Decline was steady from baseline to 6 and 12 years for prevalent HL, but time‐delayed from 6 to 12 years for incident HL. Having a hearing aid did not change associations.

DISCUSSION

Findings support the notion that HL is a risk factor for cognitive decline independent of other dementia risk factors. Onset of HL preceded onset of cognitive decline.

Highlights

We examined cognitive change in prevalent and incident hearing loss.

Prevalent and incident hearing loss were associated with faster cognitive decline.

For prevalent hearing loss, decline was steady from baseline to 6 and 12 years.

Onset of hearing loss preceded the onset of cognitive decline.

Having a hearing aid did not change the observed associations.
Cascade Electrocatalytic and Thermocatalytic Reduction of CO2 to Propionaldehyde
Authors: Zhang Jie , Kang Xingsi , Yan Yuchen , Ding Xue , He Lin , Li Yanguang
Published: January 2024

Electrochemical CO2 reduction can convert CO2 to value‐added chemicals, but its selectivity toward C3+ products are very limited. One possible solution is to run the reactions in hybrid processes by coupling electrocatalysis with other catalytic routes. In this contribution, we report the cascade electrocatalytic and thermocatalytic reduction of CO2 to propionaldehyde. Using Cu(OH)2 nanowires as the precatalyst, CO2/H2O is reduced to concentrated C2H4, CO, and H2 gases in a zero‐gap membrane electrode assembly (MEA) reactor. The thermochemical hydroformylation reaction is separately investigated with a series of rhodium‐phosphine complexes. The best candidate is identified to be the one with the 1,4‐bis(diphenylphosphino)butane diphosphine ligand, which exhibits a propionaldehyde turnover number of 1148 under a mild temperature and close‐to‐atmospheric pressure. By coupling and optimizing the upstream CO2 electroreduction and downstream hydroformylation reaction, we achieve a propionaldehyde selectivity of ~38 % and a total C3 oxygenate selectivity of 44 % based on reduced CO2. These values represent a more than seven times improvement over the best prior electrochemical system alone or over two times improvement over other hybrid systems.
Peptide and Enzyme Catalysts Work in Concert in Stereoselective Cascade Reactions—Oxidation followed by Conjugate Addition
Authors: Möhler Jasper S. , Pickl Mathias , Reiter Tamara , Simić Stefan , Rackl Jonas W. , Kroutil Wolfgang , Wennemers Helma
Published: January 2024

Enzymes and peptide catalysts consist of the same building blocks but require vastly different environments to operate best. Herein, we show that an enzyme and a peptide catalyst can work together in a single reaction vessel to catalyze a two‐step cascade reaction with high chemo‐ and stereoselectivity. Abundant linear alcohols, nitroolefins, an alcohol oxidase, and a tripeptide catalyst provided chiral γ‐nitroaldehydes in aqueous buffer. High yields (up to 92 %) and stereoselectivities (up to 98 % ee) were achieved for the cascade through the rational design of the peptide catalyst and the identification of common reaction conditions.
On‐Surface Isomerization of Indigo within 1D Coordination Polymers
Authors: Xu Hongxiang , Chakraborty Ritam , Adak Abhishek Kumar , Das Arpan , Yang Biao , Meier Dennis , Riss Alexander , Reichert Joachim , Narasimhan Shobhana , Barth Johannes V. , Papageorgiou Anthoula C.
Published: January 2024

Natural products are attractive components to tailor environmentally friendly advanced new materials. We present surface‐confined metallosupramolecular engineering of coordination polymers using natural dyes as molecular building blocks: indigo and the related Tyrian purple. Both building blocks yield identical, well‐defined coordination polymers composed of (1 dehydroindigo : 1 Fe) repeat units on two different silver single crystal surfaces. These polymers are characterized atomically by submolecular resolution scanning tunnelling microscopy, bond‐resolving atomic force microscopy and X‐ray photoelectron spectroscopy. On Ag(100) and on Ag(111), the trans configuration of dehydroindigo results in N,O‐chelation in the polymer chains. On the more inert Ag(111) surface, the molecules additionally undergo thermally induced isomerization from the trans to the cis configuration and afford N,N‐ plus O,O‐chelation. Density functional theory calculations confirm that the coordination polymers of the cis‐isomers on Ag(111) and of the trans‐isomers on Ag(100) are energetically favoured. Our results demonstrate post‐synthetic linker isomerization in interfacial metal‐organic nanosystems.
Clinicopathological comparison between PTCL‐TBX21 and PTCL‐GATA3 in Japanese patients
Authors: Shimasaki Yasumasa , Miyoshi Hiroaki , Kawamoto Keisuke , Yoshida Noriaki , Mishina Tatsuzo , Nakashima Kazutaka , Imamoto Teppei , Sugio Takeshi , Yanagida Eriko , Kato Takeharu , Yamada Kyohei , Takeuchi Mai , Suzuki Takaharu , Moritsubo Mayuko , Furuta Takuya , Imaizumi Yoshitaka , Takizawa Jun , Kato Koji , Suzumiya Junji , Suzuki Ritsuro , Ohshima Koichi
Published: January 2024

Aim

Peripheral T‐cell lymphoma not otherwise specified (PTCL‐NOS) is a heterogeneous disease that can be classified into the PTCL‐TBX21 and PTCL‐GATA3 subtypes.

Methods

In this study, we compared the clinicopathological features of PTCL‐NOS in a Japanese cohort, classified using an IHC algorithm.

Results

One hundred patients with PTCL‐NOS were categorized as having PTCL‐TBX21 (n = 55), PTCL‐GATA3 (n = 24), or PTCL‐unclassified (n = 21). When comparing PTCL‐TBX21 and PTCL‐GATA3, PTCL‐TBX21 showed significantly lower CD4 positivity (p = 0.047), lower counts of high endothelial venules (p = 0.032), and a tendency for a better response to initial treatment (p = 0.088). Gene expression analysis using the nCounter system showed higher expression of tumor immunity‐related genes, such as PD‐L1, LAG3, and IDO1, in PTCL‐TBX21 than in PTCL‐GATA3. PTCL‐GATA3 had significantly worse overall survival (OS) than those with PTCL‐TBX21 (p = 0.047), although a similar tendency was observed for progression‐free survival (PFS) (p = 0.064). PTCL‐GATA3 was a prognostic factor for OS in univariate analysis (HR 2.02; 95% CI, 1.09–3.77; p = 0.027), although multivariate analysis did not show significance (HR 2.07; 95% CI, 0.93–4.61; p = 0.074). In the PFS analysis, PTCL‐GATA3 was an independent prognostic factor by univariate analysis (HR 1.96; 95% CI, 1.08–3.56; p = 0.027) and multivariate analysis (HR 2.34; 95% CI, 1.07–5.11; p = 0.032).

Conclusion

The classification of PTCL‐NOS into PTCL‐TBX21 and PTCL‐GATA3 is useful for predicting the prognosis of Japanese patients and stratifying the administration of tumor immune checkpoint inhibitors in clinical practice.
Machine learning‐based model constructed from ultrasound radiomics and clinical features for predicting HER2 status in breast cancer patients with indeterminate (2+) immunohistochemical results
Authors: Yan Meiying , Yao Jincao , Zhang Xiao , Xu Dong , Yang Chen
Published: January 2024

Background

We aimed to predict human epidermal growth factor receptor 2 (HER2) 2+ status in patients with breast cancer by constructing and validating machine learning models utilizing ultrasound (US) radiomics and clinical features.

Methods

We analyzed 203 breast cancer cases immunohistochemically determined as HER2 2+ and used fluorescence in situ hybridization (FISH) as the confirmation method. From each case, the study analyzed 840 extracted radiomics features and 11 clinicopathologic features. Cases were randomly split into training (n = 141) and validation sets (n = 62) at a 7:3 ratio. Univariate logistic regression analysis was first performed on the 11 clinicopathologic characteristics. The least absolute shrinkage and selection operator (LASSO) and decision tree (DT) techniques were employed for post‐feature selection. Finally, 19 radiomics features were utilized in logistic regression (LR) and Naive Bayesian (NB) classifiers. Model performance was gauged using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity.

Results

Our models exhibited notable diagnostic efficacy in differentiating HER2‐positive from negative breast cancer cases. In the validation sets, the LR model outperformed the NB model with an AUC of 0.860 and accuracy of 83.8% compared to NB's AUC of 0.684 and accuracy of 79.0%. The LR model demonstrated higher sensitivity (92.3% vs. 46.2%) while the NB model had a better specificity (91.8% vs. 63.3%) in the validation set.

Conclusions

Machine learning models grounded on radiomics efficiently predicted IHC HER2 2+ status in breast cancer patients, suggesting potential enhancements in clinical decision‐making for treatment and management.
Eosin‐G and ethyl eosin dye sensitized CdS nanowires towards dye sensitized solar cells applications
Authors: Khodiyar Bhoomi , Mendhe Avinash C. , Deshmukh Tushar B. , Sankapal Babasaheb R.
Published: January 2024

One dimensional (1‐D) CdS nanowires have been grown through a low temperature chemical route and have been sensitized with eosin‐G and ethyl eosin dyes to broaden the absorption spectrum of CdS and to enhance the photoelectrochemical (PEC) performance under illumination. The used method is advantageous due to its simplicity, low cost, scalability, and controllability. Interestingly, eosin‐G and ethyl eosin dyes yield nearly four‐ and six‐fold increase in device efficiency compared to bare CdS when tested in dye‐sensitized solar cell assembly. Structural, surface morphological, optical, and surface wettability studies have been formulated for CdS, whereas identification of materials along with PEC investigations were conducted through current density–voltage (J‐V), external quantum efficiency (EQE), characteristics under the illumination of 94.6 mW/cm2 (AM 1.5G), and electrochemical impedance spectroscopy (EIS).
Facile Synthesis of Novel Ti2C Nano Bipyramids for Photothermal and Photodynamic Therapy of Breast Cancer
Authors: Ali Israt , Chang Li‐Mei , Farheen Jabeen , Huang Jiandong , Gu Zhi‐Gang
Published: January 2024

Photo‐responsive synergetic therapeutics achieved significant attraction in cancer theranostic due to the versatile characteristics of nanomaterials. There have been substantial efforts in developing the simplest nano‐design with exceptional synergistic properties and multifunctionalities. In this work, biocompatible Ti2C MXene nano bipyramids (MNBPs) were synthesized by hydrothermal method with dual functionalities of photothermal and photodynamic therapies. The MNBPs shape was obtained from two‐dimensional (2D) Ti2C nanosheets by controlling the temperature of the reaction mixture. The structure of these Ti2C MNBPs was characterized by a high‐resolution transmission electron microscope, scanning electron microscope, atomic force microscope, X‐ray photoelectron spectroscopy, and X‐ray diffraction. The Ti2C NBPs have shown exceptional photothermal properties with increased temperature to 72.3 °C under 808 nm laser irradiation. The designed nano bipyramids demonstrated excellent cellular uptake and biocompatibility. The Ti2C NBP has established a remarkable photothermal therapy (PTT) effect against 4T1 breast cancer cells. Moreover, Ti2C NBPs showed a profound response to UV light (6 mW/cm2) and produced reactive oxygen species, making them useful for photodynamic therapy (PDT). These in‐vitro studies pave a new path to tune the properties of photo‐responsive MXene nanosheets, indicating a potential use in biomedical applications.
Clinical Pharmacology Approaches to Support Approval of New Routes of Administration for Therapeutic Proteins
Authors: Wang Yow‐Ming C. , Ji Ping , Hariharan Sudharshan , Wang Jie , Okusanya Olanrewaju , AbuAsal Bilal , Zhu Hao , Madabushi Rajanikanth , Huang Shiew Mei , Zineh Issam
Published: January 2024

Intravenous or subcutaneous routes of administration (ROAs) are common dosing routes for therapeutic proteins. Eleven therapeutic proteins with approval for one ROA have subsequently received approval for a second ROA. The clinical programs supporting the second ROA consistently leveraged data from the first ROA and included studies that characterized the pharmacokinetics (PKs) of the drug administered by the new ROA to identify an appropriate dosage regimen. The selected dosing regimen was then further evaluated in clinical trials designed with various primary end points. All programs implemented model‐informed drug development approaches to ensure that the selected regimens would achieve comparable systemic exposures (PK‐based bridging) or pharmacodynamic (PD) responses (PD‐based bridging) as the reference ROA. To support the approval of a second ROA, these programs either demonstrated noninferiority in PK, PD, and/or clinical end points for the second ROA, or established efficacy and safety through a comparison to a placebo treatment. The accumulative examples showed that clinical trials which provided the primary evidence to support approvals of the second ROA generally demonstrated noninferiority in the systemic exposures regardless of being specified as an end point or not in the study protocols. The experience to date supports the use of PK‐ and PD‐based bridging approaches not only in the selection of dosing regimens for a second ROA to be tested in clinical studies, but also for providing evidence of effectiveness to support approval, when appropriate.
Between commitment and reality: A critical examination of Jordan's adherence to the New York Convention 1958
Authors: Tarawneh Mosleh A. , Alhasan Tariq K.
Published: January 2024

This study critically evaluates Jordan's bifurcated approach to the enforcement of arbitral awards, with an emphasis on its domestic laws and international obligations under the New York Convention. Utilizing a rigorous methodology that melds doctrinal scrutiny with comparative legal analysis, the research delves into Jordan's Arbitration Law 31 of 2001, its subsequent amendments, and the Enforcement of Foreign Judgments Law 8 of 1952. The analysis reveals a marked incongruence between Jordan's national legal frameworks for recognizing and enforcing foreign arbitral awards and its commitments under Article 3 of the New York Convention. The study further quantifies the financial and procedural barriers erected by Jordan's stratified judicial system, contrasting them with universally accepted benchmarks. Informed by international jurisprudence, the research proffers targeted policy recommendations designed to harmonize Jordan's arbitration regulations with prevailing pro‐enforcement international standards. This investigation fills a scholarly void and offers pragmatic, timely solutions, thereby contributing to the global dialogue on compliance with international arbitration norms, particularly from a Jordanian vantage point.
Copeptin and the syndrome of inappropriate antidiuresis (SIAD) after pituitary transsphenoidal surgery
Authors: Efthymiadis Agathoklis , Pofi Riccardo , Rostom Hussam , James Tim , Shine Brian , Guha Nish , Cudlip Simon , Christ‐Crain Mirjam , Pal Aparna
Published: January 2024

Objective

This study evaluates the predictive value of copeptin for syndrome of inappropriate antidiuresis (SIAD) postpituitary transsphenoidal surgery (TSS).

Design

Data from 133 consecutive patients undergoing TSS (November 2017–October 2022) at Oxford University Hospitals NHS trust are presented in this retrospective study.

Methods

Logistic regression (LR) and receiver operating characteristic (ROC) curves were performed to evaluate the diagnostic utility of copeptin. The Mann–Whitney U test was used to compare copeptin levels between the SIAD and no SIAD groups.

Results

Fourteen patients (10.8%) developed SIAD. Copeptin was available in 121, 53 and 87 patients for Days 1, 241 and 8 post‐TSS, respectively. LR for Day 1 copeptin to predict SIAD gave an odds ratio (OR) of 1.0 (95%CI 42 0.84–1.20, p = .99), area under‐ROC curve (AUC) was 0.49; Day 2 copeptin OR was 0.65 (95%CI 0.39–1.19, 43 p = .77), AUC was 0.57 LR for Day 1 sodium to predict SIAD gave an odds ratio (OR) of 1.0 (95%CI 0.85–1.21, p = .99), AUC was 0.50.

Conclusions

In conclusion, our data provide no evidence for copeptin as a predictive marker for post‐TSS SIAD.
Hyphal‐associated protein expression is crucial for Candida albicans‐induced eicosanoid biosynthesis in immune cells
Authors: Schimanski Jana , Gresnigt Mark S. , Brunner Elena , Werz Oliver , Hube Bernhard , Garscha Ulrike
Published: January 2024

Candida albicans causes opportunistic infections ranging from mucosal mycoses to life‐threatening systemic infections in immunocompromised patients. During C. albicans infection, leukotrienes and prostaglandins are formed from arachidonic acid by 5‐lipoxygenase (5‐LOX) and cyclooxygenases, respectively to amplify inflammatory conditions, but also to initiate macrophage infiltration to achieve tissue homeostasis. Since less is known about the cellular mechanisms triggering such lipid mediator biosynthesis, we investigated the eicosanoid formation in monocyte‐derived M1 and M2 macrophages, neutrophils and HEK293 cells transfected with 5‐LOX and 5‐LOX‐activating protein (FLAP) in response to C. albicans yeast or hyphae. Leukotriene biosynthesis was exclusively induced by hyphae in neutrophils and macrophages, whereas prostaglandin E2 was also formed in response to yeast cells by M1 macrophages. Eicosanoid biosynthesis was significantly higher in M1 compared to M2 macrophages. In HEK_5‐LOX/FLAP cells only hyphae activated the essential 5‐LOX translocation to the nuclear membrane. Using yeast‐locked C. albicans mutants, we demonstrated that hyphal‐associated protein expression is critical in eicosanoid formation. For neutrophils and HEK_5‐LOX/FLAP cells, hyphal wall protein 1 was identified as the essential surface protein that stimulates leukotriene biosynthesis. In summary, our data suggest that hyphal‐associated proteins of C. albicans are central triggers of eicosanoid biosynthesis in human phagocytes.
Stimuli‐responsive linkers and their application in molecular imaging
Authors: Wang Jing , Liu Meng , Zhang Xinyue , Wang Xinning , Xiong Menghua , Luo Dong
Published: January 2024

Molecular imaging is a non‐invasive imaging method that is widely used for visualization and detection of biological events at cellular or molecular levels. Stimuli‐responsive linkers that can be selectively cleaved by specific biomarkers at desired sites to release or activate imaging agents are appealing tools to improve the specificity, sensitivity, and efficacy of molecular imaging. This review summarizes the recent advances of stimuli‐responsive linkers and their application in molecular imaging, highlighting the potential of these linkers in the design of activatable molecular imaging probes. It is hoped that this review could inspire more research interests in the development of responsive linkers and associated imaging applications.
Forecasting food price inflation during global crises
Authors: Toledo Patricia , Duncan Roberto
Published: January 2024

In this paper, we consider the forecasting of domestic food price inflation (DFPI) using global indicators, with emphasis on episodes of macroeconomic turbulence, namely, the Global Financial Crisis (GFC) and the COVID‐19 pandemic and its subsequent repercussions. Our monthly dataset covers about two decades for more than a hundred economies. We employ dynamic model averaging (DMA) to tackle both model uncertainty and parameter instability and produce pseudo out‐of‐sample forecasts. Thus, we are able to focus on the forecasting ability of the global predictors of DFPI before and during the global crises. We find evidence that the DMA specification tends to outperform statistical models frequently used in the literature such as random walks, autoregressive models, and time‐varying parameter models, especially during global crises. We also identify the most successful predictors during the crises using their posterior probabilities of inclusion. By comparing the distributions of such probabilities, we find that the international food price inflation is the most useful predictor of DFPI for numerous countries during both crises. Other indicators such as domestic CPI inflation as well as the international inflation of agricultural commodities, fertilizers, and other food categories improved their forecasting ability, particularly during the COVID‐19 period.
Health insurance and child mortality: Evidence from India
Authors: Aiyar Anaka , Sunder Naveen
Published: January 2024

Although less than a third of the population in developing countries is covered by health insurance, the number has been on the rise. Many countries have implemented national insurance policies in the past decade. However, there is limited evidence on their impact on child mortality in low‐ and middle‐income contexts. Here we document the child mortality reducing effects of an at‐scale national level health insurance policy in India. The Rashtriya Swasthya Bima Yojana (RSBY), was rolled out across India between 2008 and 2013. Leveraging the temporal and spatial variation in program implementation, we demonstrate that it lowered infant mortality by 6% and child under five mortality by 5%. The effects are largely concentrated among urban poor households. In terms of mechanisms, we find that the program effects seem to be driven by increased usage of reproductive health services by mothers. We also demonstrate a rise in usage of complementary health services that were were not covered under the policy (such as child immunizations), which suggests that RSBY had significant positive spillover effects on health care usage.
Operative technique: Pectoralis major flap with rib
Authors: Lesh Randy W. , Hellums Ryan N. , Pichardo Priscilla , Gladfelter Madison , Purdy Nicholas C.
Published: January 2024

The osteomyocutaneous pectoralis major flap was first described in 1980 and provides a single stage reconstructive option for poor free flap or pectoralis major flap with reconstruction plate candidates requiring bony reconstruction. The flap provides good functional and cosmetic outcomes in appropriately selected patients. We describe the indications and operative techinique for harvesting this flap in written and video format.
Building a sustainable free flap program in a resource‐limited setting: A 12‐year humanitarian effort
Authors: Prasad Kavita , Peterson Nathaniel , Nolen David , Macharia Chege , Mannion Kyle , Rohde Sarah , Sinard Robert
Published: January 2024

Background

We present a sustainable complex reconstructive program built through 12 years of surgical outreach work at Kijabe Hospital in Kenya.

Methods

Retrospective chart review and anecdotal experiences.

Results

In 2011, surgeons from a US‐medical center performed Kijabe Hospital's first 3 successful free flap surgeries. Since then, they have returned 7 times, performing a total of 31 tumor excisions with microvascular reconstruction. One flap failure occurred that was reconstructed on a subsequent trip. In 2013, a US‐trained missionary surgeon and a Kenyan‐trained general surgeon began working with the visiting team with the goal of performing these surgeries independently. In 2016 they performed their first independent free flap reconstruction and have since performed 32 independent cases with only three flap losses. Establishing infrastructure, staff education, selective patient criteria, and continuous communication are the factors that enabled the success of this program.

Conclusions

Establishing a successful microvascular reconstruction program in a resource‐limited setting is feasible.
Cross‐cultural adaptation and clinical application of the Perth Empathy Scale
Authors: Ye Qingying , Liu Yang , Zhang Siyu , Ni Ke , Fu Sufen , Dou Wenjie , Wei Wei , Li Bao‐Ming , Preece David A. , Cai Xin‐Lu
Published: January 2024

Objective

Alterations of empathy have been observed in patients with various mental disorders. The Perth Empathy Scale (PES) was recently developed to measure a multidimensional construct of empathy across positive and negative emotions. However, its psychometric properties and clinical applications have not been examined in the Chinese context.

Methods

The Chinese version of the PES was developed and administered to a large Chinese sample (n = 1090). Factor structure, internal consistency, test–retest reliability, and convergent, discriminant, as well as concurrent validity were examined. Moreover, 50 patients with major depressive disorder (MDD) and 50 healthy controls were recruited to explore the clinical utility of the PES.

Results

Confirmatory factor analyses supported a theoretically congruent three‐factor structure of empathy, namely Cognitive Empathy, Negative Affective Empathy and Positive Affective Empathy. The PES showed good to excellent internal consistency reliability, good convergent and discriminant validity, acceptable concurrent validity, and moderate to high test–retest reliability. Patients with MDD had significantly lower PES scores compared to healthy controls. Linear discriminant function comprised of the three factors correctly differentiated 71% of participants, which further verified the clinical utility of the PES.

Conclusions

Our findings indicated that the Chinese version of the PES is a reliable and valid instrument to measure cognitive and affective empathy across negative and positive emotions, and could therefore be used in both research and clinical practice.
Characterization of antibody‐dependent cellular phagocytosis in patients infected with hepatitis C virus with different clinical outcomes
Authors: Adhikari Anurag , Abayasingam Arunasingam , Brasher Nicholas A. , Kim Ha Na , Lord Megan , Agapiou David , Maher Lisa , Rodrigo Chaturaka , Lloyd Andrew R. , Bull Rowena A. , Tedla Nicodemus
Published: January 2024

Early neutralizing antibodies against hepatitis C virus (HCV) and CD8 + T cell effector responses can lead to viral clearance. However, these functions alone are not sufficient to protect patients against HCV infection, thus undefined additional antiviral immune mechanisms are required. In recent years, Fc‐receptor‐dependent antibody effector functions, particularly, antibody‐dependent cellular phagocytosis (ADCP) were shown to offer immune protection against several RNA viruses. However, its development and clinical role in patients with HCV infection remain unknown. In this study, we found that patients with chronic GT1a or GT3a HCV infection had significantly higher concentrations of anti‐envelope 2 (E2) antibodies, predominantly IgG1 subclass, than patients that cleared the viruses while the latter had antibodies with higher affinities. 97% of the patients with HCV had measurable ADCP of whom patients with chronic disease showed significantly higher ADCP than those who naturally cleared the virus. Epitope mapping studies showed that patients with antibodies that target antigenic domains on the HCV E2 protein that are known to associate with neutralization function are also strongly associated with ADCP, suggesting antibodies with overlapping/dual functions. Correlation studies showed that ADCP significantly correlated with plasma anti‐E2 antibody levels and neutralization function regardless of clinical outcome and genotype of infecting virus, while a significant correlation between ADCP and affinity was only evident in patients that cleared the virus. These results suggest ADCP was mostly driven by antibody titer in patients with chronic disease while maintained in clearers due to the quality (affinity) of their anti‐E2 antibodies despite having lower antibody titers.
A novel approach for evaluation of CMIP6 GCMs in simulating temperature and precipitation extremes of Pakistan
Authors: Ali Zulfiqar , Hamed Mohammad Magdy , Muhammad Mohd Khairul Idlan , Shahid Shamsuddin
Published: January 2024

The study used a hybrid approach to evaluate the performance of 20 global climate models (GCMs) from CMIP6 in reproducing 20 extreme temperature and precipitation indices over Pakistan. This study first analysed the future simulations of extremes and discarded the GCMs whose projections fell outside the 95% confidence interval. The remaining GCMs' performance was evaluated using the Kling Gupta Efficiency‐based criteria. The changes in extreme climatic events in Pakistan were projected using the multi‐model ensemble (MME) median of the selected GCMs for four shared socioeconomic pathways (SSPs) in two future periods, 2020–2059 and 2060–2099. Four GCMs' showed inconsistency in projecting future climatic extremes and were discarded initially. The past performance of the remaining GCMs revealed EC‐Earth3‐Veg‐LR, GFDL‐ESM4, MRI‐ESM2‐0 and NOR‐ESM2‐MM to be effective in reproducing extreme indices for the historical period. The MME median of the selected GCMs showed a gradual increase in most of the temperature and precipitation extreme indices in the future periods for all SSPs across the country. Specifically, it showed a higher increase in daily maximum temperature (TXx) by 4.5–5°C, daily minimum temperature (TNn) by more than 4.5°C, consecutive days with a temperature higher than the 95th percentile (WSDI) by >160 days, one‐day maximum rainfall by 9–15 mm and days with precipitation above the 95th percentile by >50 mm in northern high‐elevated areas during 2060–2099 for SSP585. Similarly, a higher increase in TXx by 4.5–5°C, TNn by >4.5°C, WSDI by 140 days and tropical nights by 40–60 days was also found in the western arid region during 2060–2099 for SSP585. The study highlights that northern high‐elevated and western arid regions are at a higher risk of extreme temperatures and precipitation due to climate change.
International tourists' perceptions of Myanmar as a tourist destination in the crisis: A comparative study among three continents
Authors: Kang Soon Hwa , Lee Gyu Tae , Huh Chang , Lee Myong Jae
Published: January 2024

Myanmar has emerged as a popular tourist destination following its recent political transformation, with the Travel and Tourism sector contributing significantly to the country's GDP. However, the outbreak of the COVID‐19 pandemic posed numerous challenges for the global tourism industry and Myanmar, including travel restrictions, border closures, and health concerns. This study examines the levels of satisfaction and inconvenience experienced by tourists from Asia, Europe, and America who visited Myanmar during the early stages of the pandemic. A sample of 202 tourists was collected from Yangon and Myeik, two prominent tourist destinations in Myanmar. Various statistical tests were employed to analyze international tourists' perceptions of Myanmar tourism. The findings revealed that tourists from all three regions expressed satisfaction with the natural scenery, historical sites and architectural design, and traditional costumes offered by Myanmar. The implications of the study are discussed.
Impacts of supply and demand shocks on abnormal fluctuation of stock price: An analysis of US–China trade friction
Authors: Li Jinwei , Wei Qian , Jiang Tianshu
Published: January 2024

This paper aims to study the impact of supply and demand shocks on abnormal fluctuation of stock price. We use event study and regression analysis methods to explain why the supply and demand shocks caused by US–China trade friction in targeting industries can affect the whole Chinese securities market. Our findings reveal a direct effect of shocks that can affect the stock prices of targeted companies. Additionally, there is a network effect in which the supply side and demand side shocks propagate upstream and downstream through the network, in turn affecting the stock prices of nontargeted companies.
Making ends meet: Unique ways Ph.D. students are covering living expenses
Authors: Arnett Autumn
Published: January 2024

Many graduate programs prohibit Ph.D. hopefuls from holding full‐time jobs, in an effort to ensure graduate students are focusing on their studies. There has been much dialogue around how difficult it is to live on the wages provided in these programs, but little has changed from a policy perspective to either offer higher pay rates for those in Ph.D. programs or more flexibility for grad students to seek outside opportunities.
Learn about the DOJ and ED's joint ‘Dear Colleague’ letter regarding webpage accessibility
Authors: Masinter Michael R.
Published: January 2024

On May 19, 2023, the U.S. Department of Justice and the Education Department released a joint “Dear Colleague” letter outlining the Section 504 and Americans With Disabilities Act accessibility obligations that govern educational institutions’ public‐facing webpages. Although the Dear Colleague letter reiterates that all public‐facing webpages should be accessible to low‐vision, hearing‐impaired, and limited motor control users, it offers little new guidance on compliance timelines, suggesting instead that the Departments will afford some flexibility to institutions that have not yet come into compliance. Thus, while institutions already should have ensured as a matter of self‐interest that critical public‐facing webpages — including those related to applications, marketing, and news announcements — are accessible, institutions need not scour all public‐facing webpages to immediately root out inaccessible archival material.