bluuebunny/crossref_metadata_2025 huggingface dataset:
FDA Approval Summary: Alpelisib for PIK3CA-Related Overgrowth Spectrum
Authors: Singh Sonia , Bradford Diana , Li Xiaoxue , Mishra-Kalyani Pallavi S. , Shen Yuan-Li , Wang Lingshan , Zhao Hong , Xiong Ye , Liu Jiang , Charlab Rosane , Kraft Jeffrey , Khasar Sachia , Miller Claudia P. , Rivera Donna R. , Kluetz Paul G. , Pazdur Richard , Beaver Julia A. , Singh Harpreet , Donoghue Martha
Published: August 2023

On April 5, 2022, FDA granted accelerated approval to alpelisib for the treatment of adult and pediatric patients 2 years of age and older with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy. Efficacy was evaluated using real-world data (RWD) from EPIK-P1 (NCT04285723), a single-arm clinical study in patients 2 years of age and older with severe or life-threatening PROS who received alpelisib as part of an expanded access program (EAP) for compassionate use. The primary endpoint was confirmed radiologic response rate at week 24 as determined by blinded independent central review (BICR), using volumetric-based criteria given the atypical growth pattern and irregular shape of PROS lesions. Radiologic response was defined as a ≥20% reduction from baseline in the sum of measurable target lesion volume in up to three lesions. Of the 37 patients in the efficacy population, 27% [95% confidence interval (CI), 14–44] had a radiologic response at week 24. Duration of response (DOR) was an additional efficacy outcome measure, and among responders, 60% had a response lasting ≥12 months. Furthermore, supportive clinical documentation suggested early signals of clinical benefit (i.e., improvement in PROS-related signs and symptoms). The most common (≥10%) adverse reactions were diarrhea, stomatitis, and hyperglycemia.
Cancer-Immunity Marker RNA Expression Levels across Gynecologic Cancers: Implications for Immunotherapy
Authors: Jou Jessica , Kato Shumei , Miyashita Hirotaka , Thangathurai Kartheeswaran , Pabla Sarabjot , DePietro Paul , Nesline Mary K. , Conroy Jeffrey M. , Rubin Eitan , Eskander Ramez N. , Kurzrock Razelle
Published: August 2023

Our objective was to characterize cancer-immunity marker expression in gynecologic cancers and compare immune landscapes between gynecologic tumor subtypes and with nongynecologic solid tumors. RNA expression levels of 51 cancer-immunity markers were analyzed in patients with gynecologic cancers versus nongynecologic cancers, and normalized to a reference population of 735 control cancers, ranked from 0 to 100, and categorized as low (0–24), moderate (25–74), or high (75–100) percentile rank. Of the 72 patients studied, 43 (60%) had ovarian, 24 (33%) uterine, and 5 (7%) cervical cancer. No two immune profiles were identical according to expression rank (0–100) or rank level (low, moderate, or high). Patients with cervical cancer had significantly higher expression level ranks of immune activating, proinflammatory, tumor-infiltrating lymphocyte markers, and checkpoints than patients with uterine or ovarian cancer (P < 0.001 for all comparisons). However, there were no significant differences in immune marker expression between uterine and ovarian cancers. Tumors with PD-L1 tumor proportional score (TPS) ≥1% versus 0% had significantly higher expression levels of proinflammatory markers (58 vs. 49%, P = 0.0004). Compared to patients with nongynecologic cancers, more patients with gynecologic cancers express high levels of IDO-1 (44 vs. 13%, P < 0.001), LAG3 (35 vs. 21%, P = 0.008), and IL10 (31 vs. 15%, P = 0.002.) Patients with gynecologic cancers have complex and heterogeneous immune landscapes that are distinct from patient to patient and from other solid tumors. High levels of IDO1 and LAG3 suggest that clinical trials with IDO1 inhibitors or LAG3 inhibitors, respectively, may be warranted in gynecologic cancers.
Supplementary Table 2 from Multicellular Complex Tumor Spheroid Response to DNA Repair Inhibitors in Combination with DNA-damaging Drugs
Authors: Dexheimer Thomas S. , Coussens Nathan P. , Silvers Thomas , Wright John , Morris Joel , Doroshow James H. , Teicher Beverly A.
Published: August 2023

Table S2. Links to the PubChem assays.
Supplementary Figure 5 from Multicellular Complex Tumor Spheroid Response to DNA Repair Inhibitors in Combination with DNA-damaging Drugs
Authors: Dexheimer Thomas S. , Coussens Nathan P. , Silvers Thomas , Wright John , Morris Joel , Doroshow James H. , Teicher Beverly A.
Published: August 2023

Figure S5. Heat maps of Bliss synergy scores across the combination dose-response matrices for all twenty-six cell lines grown as multicellular complex spheroids exposed to each DNA damaging agent (A, TMZ; B, topotecan; C, trabectedin) in combination with DNA-PK inhibitors, nedisertib or VX-984.
Supplementary Figure 1 from Multicellular Complex Tumor Spheroid Response to DNA Repair Inhibitors in Combination with DNA-damaging Drugs
Authors: Dexheimer Thomas S. , Coussens Nathan P. , Silvers Thomas , Wright John , Morris Joel , Doroshow James H. , Teicher Beverly A.
Published: August 2023

Figure S1. Representative brightfield images for assay optimized cell densities from a DMSO-treated well on Day 10.
Blinded Withdrawal of Long-Term Randomized Treatment With Empagliflozin or Placebo in Patients With Heart Failure
Authors: Packer Milton , Butler Javed , Zeller Cordula , Pocock Stuart J. , Brueckmann Martina , Ferreira João Pedro , Filippatos Gerasimos , Usman Muhammad Shariq , Zannad Faiez , Anker Stefan D.
Published: August 2023

BACKGROUND:

It is not known whether the benefits of sodium-glucose cotransporter 2 inhibitors in heart failure persist after years of therapy.

METHODS:

In the EMPEROR-Reduced (Empagliflozin Outcome Trials in Chronic Heart Failure With Reduced Ejection Fraction) and EMPEROR-Preserved (Empagliflozin Outcome Trials in Chronic Heart Failure With Preserved Ejection Fraction) trials, patients with heart failure were randomly assigned (double-blind) to placebo or empagliflozin 10 mg/day for a median of 16 and 26 months, respectively. At the end of the trials, 6799 patients (placebo 3381, empagliflozin 3418) were prospectively withdrawn from treatment in a blinded manner, and, of these, 3981 patients (placebo 2020, empagliflozin 1961) underwent prespecified in-person assessments after ≈30 days off treatment.

RESULTS:

From 90 days from the start of closeout to the end of double-blind treatment, the annualized risk of cardiovascular death or hospitalization for heart failure was lower in empagliflozin-treated patients than in placebo-treated patients (10.7 [95% CI, 9.0–12.6] versus 13.5 [95% CI, 11.5–15.6] events per 100 patient-years, respectively; hazard ratio 0.76 [95% CI, 0.60–0.96]). When the study drugs were withdrawn for ≈30 days, the annualized risk of cardiovascular death or hospitalization for heart failure increased in patients withdrawn from empagliflozin but not in those withdrawn from placebo (17.0 [95% CI, 12.6–22.1] versus 14.1 [95% CI, 10.1–18.8] events per 100 patient-years for empagliflozin and placebo, respectively). The hazard ratio for the change in risk in the patients withdrawn from empagliflozin was 1.75 (95% CI, 1.20–2.54),
P
=0.0034, whereas the change in the risk in patients withdrawn from placebo was not significant (hazard ratio 1.12 [95% CI, 0.76–1.66]); time period-by-treatment interaction,
P
=0.068. After withdrawal, the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score declined by 1.6±0.4 in patients withdrawn from empagliflozin versus placebo (
P
<0.0001). Furthermore, withdrawal of empagliflozin was accompanied by increases in fasting glucose, body weight, systolic blood pressure, estimated glomerular filtration rate, N-terminal pro-hormone B-type natriuretic peptide, uric acid, and serum bicarbonate and decreases in hemoglobin and hematocrit (all
P
<0.01). These physiological and laboratory changes were the inverse of the effects of the drug seen at the start of the trials during the initiation of treatment (≈1–3 years earlier) in the same cohort of patients.

CONCLUSIONS:

These observations demonstrate a persistent effect of empagliflozin in patients with heart failure even after years of treatment, which dissipated rapidly after withdrawal of the drug.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifiers: NCT03057977 and NCT03057951.
Effect and Mechanism of CircPTPN4 Expression in Carboxylated Single-Walled Carbon Nanotubes on Renal Fibrosis
Authors: Liu Yuhan , Teng Yan , Jing Fangkun , Zhang Yanning
Published: August 2023

This research was aimed to investigate the effect of circPTPN4 overexpression in carboxylated single-walled carbon nanotubes (SWCNT-COOH) on renal fibrosis (RF) in mice. SWCNT was oxidized to SWCNT-COOH by concentrated sulfuric acid and nitric acid (3:1, v/v). After characterization
and analysis, the effect of SWCNT-COOH on erythrocyte status was detected. The RF mice (RFM) model was induced by SWCNT-COOH, normal mice as normal control (NC), and 1×108 TU/mL lenti-NC was injected into the tail vein as negative control, and 1×108 TU/mL
lenti-circPTPN4 was injected for circPTPN4 overexpression. The expression of circPTPN4 was tested by qRT-PCR. Serum creatinine (Cr), blood urea nitrogen (BUN), interleukin 1β (IL-1β), IL-6, transforming growth factor β1 (TGF-β1), kidney injury
molecule 1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) were tested by ELISA. HE, Masson, and immunohistochemistry were used to detect the pathological changes of kidney tissue. The protein expressions of collagen I (COL1), fibronectin (Fn), α-SMA, TGF-β1,
Smad3, p-Smad3, and Smad7 were tested by Western blot (WB). It presented SWCNT-COOH was successfully prepared by chemical oxidation method, with an average particle size of 98.1 nm and an average Zeta potential of −38.91 mV. SWCNT-COOH had good hydrophilicity, and did not cause aggregation
and morphology changes of red blood cells. As against NC, the expression of circPTPN4 in RFM and lenti-NC groups was decreased; the kidney coefficient was increased, and the normal structure of the kidney was abnormal, accompanied by inflammatory cell infiltration and collagen microformation;
serum Cr, BUN, IL-1β, IL-6, and TGF-β1 were increased, and KIM-1 and NGAL in renal cortex were decreased; the protein expressions of COL1, Fn, α-SMA, TGF-β1, and p-Smad3 in the kidney were increased, and the protein expression of Smad7 was decreased
(P <0.05). As against RFM, the expression of circPTPN4 in lenti-circPTPN4 group was increased; the kidney coefficient decreased and the kidney structure returned to normal; COL1, Fn, α-SMA, TGF-β1, and p-Smad3 in the kidney were decreased, and that of Smad7
was increased (P <0.05). SWCNT-COOH has good blood compatibility characteristics and can induce RF in mice. The expression of circPTPN4 was down-regulated in the RFM. Overexpression of circPTPN4 can restore the normal renal function of RFM, inhibiting the inflammatory response and
RF process.
Improving AHI Radiance Assimilation over Land with the Surface Skin Temperature Constrained by Station Observations and Its Impact for Quantitative Precipitation Forecasts
Authors: Li Xin , Zou Xiaolei , Zeng Mingjian , Zhuge Xiaoyong , Liu Weiguang
Published: August 2023

In this study, a new way to assimilate clear-sky Advanced Himawari Imager (AHI) surface-sensitive brightness temperature (TB) observations over land is investigated for improving quantitative precipitation forecasts (QPFs) in eastern China. To alleviate problems arising from inaccurate surface temperature in radiance simulations, surface station observations of land surface skin temperature (LSST) together with conventional and AMSU-A observations are assimilated to improve AHI surface-sensitive TB simulations of the Community Radiative Transfer Model (CRTM) before AHI data assimilation. First, the Gridpoint Statistical Interpolation (GSI) three-dimensional variational (3DVar) system is updated with the additional control variable of surface temperature and its background error covariances. Second, surface temperature and emissivity sensitivity checks are designed for the quality control of the surface-sensitive AHI channels. Finally, the impacts of a two-time data assimilation strategy are assessed for a local convection rainfall case and a synoptic-scale precipitation case. The experiment in which AHI data are assimilated after assimilating LSST data (ExpL2) outperforms the traditional experiment in which the LSST is not updated (ExpL) in terms of its 24-h QPF skill score. A better description of atmospheric instability and moisture convergence forcing is obtained in ExpL2 than in ExpL. Both experiments show additional low-level temperature and humidity adjustments compared to the experiment that does not assimilate AHI surface-sensitive channels (ExpNL). Lower AHI TB simulation biases are found in the ExpL2 experiment, which improve the analyzed field and subsequent QPFs. The results in this study suggest the importance of proper utilization of LSST observations for AHI surface-sensitive TB assimilations over land.
Electrophysiological findings in migraine may reflect abnormal synaptic plasticity mechanisms: A narrative review
Authors: Puledda Francesca , Viganò Alessandro , Sebastianelli Gabriele , Parisi Vincenzo , Hsiao Fu-Jung , Wang Shuu-Jiun , Chen Wei-Ta , Massimini Marcello , Coppola Gianluca
Published: August 2023

Background

The cyclical brain disorder of sensory processing accompanying migraine phases lacks an explanatory unified theory.

Methods

We searched Pubmed for non-invasive neurophysiological studies on migraine and related conditions using transcranial magnetic stimulation, electroencephalography, visual and somatosensory evoked potentials. We summarized the literature, reviewed methods, and proposed a unified theory for the pathophysiology of electrophysiological abnormalities underlying migraine recurrence.

Results

All electrophysiological modalities have determined specific changes in brain dynamics across the different phases of the migraine cycle. Transcranial magnetic stimulation studies show unbalanced recruitment of inhibitory and excitatory circuits, more consistently in aura, which ultimately results in a substantially distorted response to neuromodulation protocols. Electroencephalography investigations highlight a steady pattern of reduced alpha and increased slow rhythms, largely located in posterior brain regions, which tends to normalize closer to the attacks. Finally, non-painful evoked potentials suggest dysfunctions in habituation mechanisms of sensory cortices that revert during ictal phases.

Conclusion

Electrophysiology shows dynamic and recurrent functional alterations within the brainstem-thalamus-cortex loop varies continuously and recurrently in migraineurs. Given the central role of these structures in the selection, elaboration, and learning of sensory information, these functional alterations suggest chronic, probably genetically determined dysfunctions of the synaptic short- and long-term learning mechanisms.
An Eco-Friendly Alternative to Plastic Cutlery and Food Packaging: A Case of Ecoware in India
Authors: Tudu Preshita Neha , Mishra Vaibhav
Published: August 2023

The nonchalant nature of plastic cutlery, its long-life period, and its durability make it a favourite among users and businesses. However, these properties also make it lethal for the environment and are an eco-disaster. This case discusses an initiative taken by a social enterprise and manufacturing company Ecoware, founded by Rhea Singhal, a pharmacologist by profession. Born in Mumbai and bought up in Dubai and London, her eco-friendly, biodegradable cutlery is an alternative to non-biodegradable single-use plastic cutlery, which, when discarded, ends up in sewage, landfills, fields and water bodies posing a threat to the environment. Moreover, Ecoware cutlery is also an alternative to commercial cutlery, which is made of plastic, has chemical or pesticide residue, binder additives, fillers, wax lining, plastic lining or coatings, or PFA (per- and poly-fluoroalkyl substances), which is generally added to tableware and food packing to offer resistance to oil, grease and moisture.

This Ecoware case examines the correlation between sustainability and marketing, with a particular emphasis on sustainability marketing. It delves into Ecoware’s marketing mix strategy and explores the obstacles the company has encountered regarding pricing, environmental awareness and the general lack of understanding regarding the detrimental effects of plastic cutlery.
Vietnam’s Responses to Dementia – An Assessment of Service Delivery
Authors: Kosowicz Leona , Tran Kham Van , Brodaty Henry , Roughead Elizabeth , Esterman Adrian , Hinton Ladson , Kim Giang Bao , Kurrle Susan , Dang Thu Ha , Crotty Maria , Gilbert Andrew , Tan Esther , Nguyen Tuan Anh
Published: August 2023

Background

This study was conducted to assess Vietnam’s dementia service delivery.

Methods

Using WHO methodology, website searches of key organisations focused on three aspects of Vietnam’s healthcare system: (1) Health and social workforce; (2) Services, supports and treatment programs; and (3) Promotion of awareness and understanding. Data were analysed using content analysis.

Results

While key members of the healthcare workforce receive some education in dementia competencies during their training, the skill-mix of staff in the current workforce appears inadequate to address the complex needs of people with dementia. Although Vietnam’s general healthcare system comprises a good variety of service types, there is a lack of dementia-specific services. Available diagnosis and treatment services are concentrated in the hospital system and are mainly located in metropolitan areas, impacting their accessibility. While both community-based and institutional long-term care is available, institutional care is not universally accessible and home-based care is mainly provided by family carers who don’t have access to dementia care training. There is no active dementia prevention or public awareness campaign.

Conclusions

To improve the ability of Vietnam’s service delivery to meet the needs of people with dementia and their carers, the skill-mix of the healthcare workforce should be strengthened by ensuring that dementia core competencies are embedded within undergraduate and graduate education programs and making post-qualification dementia care training available. The capacity of existing community-level health and social services should be expanded to ensure that integrated, specialised and comprehensive health and social services are accessible to all people with dementia. Expanding access to institutional long-term care and making dementia education available to family and other informal carers could increase choice and improve quality of care. Finally, Vietnam could look to other countries in the region with regards to the development of a dementia prevention and public awareness campaign.
Emotional Appraisal, Psychological Distance and Construal Level: Implications for Cognitive Reappraisal
Authors: Abraham Damon , Powers John P. , McRae Kateri
Published: August 2023

Construal-level theory emphasizes that representing events at greater spatial, temporal, social, or hypothetical distance results in processing information at high construal levels (more conceptual, abstract). We posit that psychological distance and construal level are somewhat separable constructs, and can have different effects on emotion, and therefore, emotion regulation. We argue that psychological distance influences emotional appraisal, such that increasing distance results in lower emotion intensity, which can be leveraged to down-regulate emotions. However, we consider construal level a mindset, which can occur with either high or low psychological distance. Furthermore, we argue that compared with psychological distance, construal level has a more nuanced relationship with emotion, and changing construal level for the purpose of changing emotion also requires considering the construal level of one's emotion-regulation goals.
Elevation of serum lactate dehydrogenase during methylprednisolone pulse therapy as a predictor of high mortality in acute respiratory failure: A single-center, retrospective study
Authors: Kanaoka Kensuke , Minami Seigo
Published: August 2023

Background:

Corticosteroids are common treatments in certain diseases that cause acute respiratory failure (ARF) and are sometimes administered empirically for patients with critical ARF. Associations between changes in clinical parameters following initiation of steroid pulse therapy and mortality in patients with ARF have not been previously investigated.

Methods:

This was a single-center and retrospective cohort study. Parameters on the day of methylprednisolone pulse therapy initiation (day 1) and the day following the end of methylprednisolone therapy (day 4) in patients who were admitted because of ARF and underwent methylprednisolone pulse therapy between October 2008 and July 2021 were reviewed.

Results:

A total of 98 patients were included in our analysis, and 45 (46%) died at our hospital. Change in lactate dehydrogenase (LDH) from day 1 to day 4 (ΔLDH) was significantly higher in the in-hospital death group than in the survival group (−68 IU/L in the survival group versus 46 IU/L in the in-hospital death group, p < 0.01). Multivariate logistic analyses showed that age >75 years old (odds ratio (OR), 3.88; 95% confidence interval (CI), 1.38–10.9; p < 0.01), previously diagnosed interstitial lung disease (OR, 3.43; 95% CI, 1.10–10.7; p = 0.03), ΔLDH > 0 (OR, 6.47; 95% CI, 2.30–18.2; p < 0.01), and ΔSequential Organ Failure Assessment score > 0 (OR, 3.06; 95% CI, 1.10–8.51; p = 0.03) were significantly associated with in-hospital mortality.

Conclusions:

This study showed that elevation of serum LDH level during methylprednisolone pulse therapy was a predictive factor for high in-hospital mortality in patients with ARF.
Semantic temporality analysis: A computational approach to time in English and German texts
Authors: Watanabe Kohei , Sältzer Marius
Published: August 2023

Temporality is an important aspect of political discourse. Politicians and policymakers attempt to construct the past and the future to gain power, legitimize their policies, claim success for themselves and blame others. To make computational analysis of temporality more accessible, we develop a new methodology using a semisupervised machine-learning algorithm called Latent Semantic Scaling. Only with a set of common verbs in the past perfect and future tense as seed words, the algorithm estimates the temporality of all other words. We demonstrate that it can identify temporal orientation of English and German sentences from election manifestos around 60–70% accurately, which is comparable to the results from a recent study based on supervised machine-learning algorithms. We also apply it to Twitter posts by German political parties to reveal temporal orientation of policy issues.
Overall and patient-specific comparative effectiveness of dimethyl fumarate versus teriflunomide: A novel approach to precision medicine applied to the German NeuroTrans Data Multiple Sclerosis Registry
Authors: Jiang Xiaotong , Simoneau Gabrielle , Zuercher Mel , Heer Yanic , van Hoevell Philip , Harrington Adrian , Castro-Borrero Wanda , de Moor Carl , Pellegrini Fabio , Tian Lu , Bergmann Arnfin , Braune Stefan
Published: August 2023

Background

Multiple sclerosis (MS) comparative effectiveness research needs to go beyond average treatment effects (ATEs) and post-host subgroup analyses.

Objective

This retrospective study assessed overall and patient-specific effects of dimethyl fumarate (DMF) versus teriflunomide (TERI) in patients with relapsing-remitting MS.

Methods

A novel precision medicine (PM) scoring approach leverages advanced machine learning methods and adjusts for imbalances in baseline characteristics between patients receiving different treatments. Using the German NeuroTransData registry, we implemented and internally validated different scoring systems to distinguish patient-specific effects of DMF relative to TERI based on annualized relapse rates, time to first relapse, and time to confirmed disease progression.

Results

Among 2791 patients, there was superior ATE of DMF versus TERI for the two relapse-related endpoints ( p = 0.037 and 0.018). Low to moderate signals of treatment effect heterogeneity were detected according to individualized scores. A MS patient subgroup was identified for whom DMF was more effective than TERI ( p = 0.013): older (45 versus 38 years), longer MS duration (110 versus 50 months), not newly diagnosed (74% versus 40%), and no prior glatiramer acetate usage (35% versus 5%).

Conclusion

The implemented approach can disentangle prognostic differences from treatment effect heterogeneity and provide unbiased patient-specific profiling of comparative effectiveness based on real-world data.
Impact of Biologic Augmentation on Revision Surgery Rates After Meniscus Repair: A Matched-Cohort Analysis of 3420 Patients
Authors: Dancy Malik E. , Marigi Erick M. , Krych Aaron J. , Werner Brian C. , Camp Christopher L.
Published: August 2023

Background:

Platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC) have gained popularity in recent years as biologic approaches to potentially augment healing after meniscus repair. There have been few studies comparing outcomes in patients undergoing meniscus repair with versus without biologic augmentation and, furthermore, little clarity on the role of biologic augmentation for meniscus repairs performed with concomitant anterior cruciate ligament reconstruction (ACLR).

Purpose:

To determine the association of BMAC or PRP augmentation with revision surgery after both isolated meniscus repair and meniscus repair performed concomitantly with ACLR.

Study Design:

Cohort study; Level of evidence, 3.

Methods:

The PearlDiver Mariner dataset was queried to identify all patients who underwent primary meniscus repair, both with and without concomitant ACLR, and who received ipsilateral BMAC or PRP at the time of surgery. Patients who underwent similar surgery but without BMAC or PRP augmentation were then identified and matched in a 5:1 ratio according to age, sex, body mass index, and various comorbidities to 3 separate BMAC/PRP augmentation groups: overall cohort (with and without ACLR), repair with concomitant ACLR, and isolated repair. The primary outcome was revision meniscus surgery (meniscectomy or revision meniscus repair).

Results:

Overall, 3420 patients (570 with BMAC/PRP augmentation; 2850 matched controls without augmentation) were included. There were no significant differences in the reported demographics or comorbidities between any of the BMAC/PRP groups and their respective matched controls ( P > .05 for all comparisons). There was no difference in revision rate between BMAC/PRP-augmented isolated meniscus repairs and matched controls ( P = .235). Patients who underwent BMAC/PRP-augmented meniscus repair with concomitant ACLR experienced a significantly lower incidence of revision surgery compared with matched controls without BMAC/PRP augmentation (5.2% vs 7.9% respectively; odds ratio, 0.41; 95% CI, 0.27-0.63; P < .001), but the number of revisions was relatively small.

Conclusion:

There was no association between BMAC or PRP augmentation and the incidence of revision surgery after isolated primary meniscus repair. There was a statistically significant decrease in the rate of revision meniscus surgery when BMAC or PRP was used to augment meniscus repairs in the setting of concurrent ACLR; however, the overall revision rates were small.
Scope-shifting: Bureaucracy, Energy Justice and the Dakota Access Pipeline
Authors: Bondi Brittany , Horowitz Leah S.
Published: August 2023

Through a study of the U.S. Army Corps of Engineers' (USACE) environmental assessment (EA) of the Dakota Access Pipeline's crossing of Lake Oahe near the Standing Rock Sioux Reservation, this paper explores regulatory agencies’ “interpretive implementation.” We find that, in implementing the National Environmental Policy Act and Executive Order 12898 on Environmental Justice, USACE “scope-shifted”—facultatively expanding and contracting the scopes of its spatial, scientific and cost–benefit impact analyses—to expedite industrial expansion, contravening the policies’ original intents. In doing so, USACE's EA created various energy injustices by excluding local tribes (especially the Standing Rock Sioux and Cheyenne River Sioux Tribes) and their concerns, e.g. treaty rights, local histories, climate change and especially potential oil spills with impacts on human health and subsistence resources. We analyze this scope-shifting through the lens of Karl Polayni's double movement between socioenvironmental protections and capitalist development. We elaborate this framework further via a triple-helix model that analyses ideologies, power relations and policies (here further complicated by both “law” and “interpretation” threads), as three intertwined strands that pull with or against each other, jointly progressing toward greater rights for vulnerable communities, “retrograding” toward earlier, oppressive conditions or simply stagnating. Ultimately, we argue that understanding scope-shifting and other forms of interpretive implementation as threads within the triple-helix policy strand, in dynamic tension or synchrony with other threads and strands, can help explicate agency decision-making processes. We hope that this conceptualization can elucidate the capacity of seemingly mundane bureaucratic practices for exacerbating, or potentially alleviating, energy injustice.
Early milk-feeding regimes in calves exert long-term effects on the development of ovarian granulosa cells
Authors: Röttgen Volker , Tümmler Lisa-Maria , Koczan Dirk , Rebl Alexander , Kuhla Björn , Vanselow Jens , Baufeld Anja
Published: August 2023

Background

Nutrition has not only an impact on the general wellbeing of an animal but can also affect reproductive processes. In cattle, feeding regimes can influence the age of puberty onset and alter gonadal development. We analyzed effects of different milk replacer (MR) feeding regimes during rearing on ovarian physiology with specific emphasis on the numbers as well as gene expression characteristics of granulosa cells (GCs) at the age of puberty onset. Two groups of calves received either 10% or 20% of bodyweight MR per day during their first 8 weeks. After weaning, both groups were fed the same mixed ration ad libitum until slaughter at 8 months.

Results

Animals of the 20% feeding group had a significantly higher body weight, but the proportion of animals having a corpus luteum at the time of slaughter was not different between groups, suggesting a similar onset of puberty. Calves of the 10% group showed a constant GC count regardless of the number of follicles (r = 0.23) whereas in the 20% group increasing numbers of GCs were detected with a higher follicle count (r = 0.71). As a first effort to find a possible molecular explanation for this unexpected limitation of GC numbers in the 10% group, we comparatively analyzed GC transcriptomes in both diet groups. The mRNA microarray analysis revealed a total of 557 differentially expressed genes comparing both groups (fold change > |1.5| and p < 0.05). OAS1X, MX2 and OAS1Z were among the top downregulated genes in the 20% vs. the 10% group, whereas top upregulated genes comprised BOLA and XCL1. All of these genes are known to be regulated by interferon. Subsequent signaling pathway analysis revealed the involvement of several immune response mechanisms in accordance with a number of interferons as upstream regulators.

Conclusions

The results indicate that the plane of MR feeding in early life has an impact on the number and physiology of GCs later in life. This might influence the overall reproductive life initiated by the onset of puberty in cattle. In addition, the observed alterations in GCs of calves fed less MR might be a consequence of interferon regulated immunological pathways.
Development of the Swedish anticholinergic burden scale (Swe-ABS)
Authors: Rube Tanja , Ecorcheville Astrid , Londos Elisabet , Modig Sara , Johansson Per
Published: August 2023

Background

Drugs with anticholinergic properties are associated with cognitive adverse effects, especially in patients vulnerable to central muscarinic antagonism. A variety of drugs show weak, moderate or strong anticholinergic effects. Therefore, the cumulative anticholinergic burden should be considered in patients with cognitive impairment. This study aimed to develop a Swedish Anticholinergic Burden Scale (Swe-ABS) to be used in health care and research.

Methods

A systematic literature review was conducted in PubMed and Ovid Embase to identify previously published tools quantifying anticholinergic drug burden (i.e., exposure). Drugs and grading scores (0–3, no to high anticholinergic activity) were extracted from identified lists. Enteral and parenteral drugs authorized in Sweden were included. Drugs with conflicting scores in the existing lists were assessed by an expert group. Two drugs that were not previously assessed were also added to the evaluation process.

Results

The systematic literature search identified the following nine anticholinergic burden scales: Anticholinergic Activity Scale, Anticholinergic Burden Classification, updated Anticholinergic Cognitive Burden scale, Anticholinergic Drug Scale, Anticholinergic Load Scale, Anticholinergic Risk Scale, updated Clinician-rated Anticholinergic Scale, German Anticholinergic Burden Scale and Korean Anticholinergic Burden Scale. A list of drugs with significant anticholinergic effects provided by The Swedish National Board of Health and Welfare was included in the process. The suggested Swe-ABS consists of 104 drugs scored as having weak, moderate or strong anticholinergic effects. Two hundred and fifty-six drugs were listed as having no anticholinergic effects based on evaluation in previous scales. In total, 62 drugs were assessed by the expert group.

Conclusions

Swe-ABS is a simplified method to quantify the anticholinergic burden and is easy to use in clinical practice. Publication of this scale might make clinicians more aware of drugs with anticholinergic properties and patients’ total anticholinergic burden. Further research is needed to validate the Swe-ABS and evaluate anticholinergic exposure versus clinically significant outcomes.
Association among peripatellar fat pad edema and related patellofemoral maltracking parameters: a case-control magnetic resonance imaging study
Authors: Lyu Liangjing , Li Yongliang , Zhong Jingyu , Yao Weiwu
Published: August 2023

Background

The peripatellar fat pads are critical for protective cushioning during movement, and their endocrine function has been shown to affect osteoarthritis. Magnetic resonance imaging (MRI) is frequently used to visualize edema of the peripatellar fat pads due to injury. In this study, we aimed to assess the relationship between peripatellar fat pad edema and patellofemoral maltracking MRI parameters and investigate the association among cases of peripatellar fat pad edema.

Methods

Age- and sex-matched peripatellar fat pad edema cases were identified and divided into superolateral Hoffa, quadriceps, and prefemoral groups. Images were assessed according to tibial tuberosity lateralization, trochlear dysplasia, patellar alta, patellar tilt, and bisect offset. McNemar’s test or paired t-tests and Spearman’s correlation were used for statistical analysis. Interobserver agreement was assessed with the intraclass correlation coefficient.

Results

Of 1210 MRI scans, 50, 68, and 42 cases were in the superolateral Hoffa, quadriceps, and prefemoral groups, respectively. Subjects with superolateral Hoffa fat pad edema had a lower lateral trochlear inclination (p = 0.028), higher Insall-Salvati (p < 0.001) and modified Insall-Salvati (p = 0.021) ratios, and lower patellotrochlear index (p < 0.001) than controls. The prefemoral group had a lower lateral trochlear inclination (p = 0.014) and higher Insall-Salvati (p < 0.001) and modified Insall-Salvati (p = 0.004) ratios compared with the control group. In contrast, the patellotrochlear index (p = 0.001) was lower. Mean patellar tilt angle (p = 0.019) and mean bisect offset (p = 0.005) were significantly different between cases and controls. The quadriceps group showed no association. Superolateral Hoffa was positively correlated with prefemoral (p < 0.001, r = 0.408) and negatively correlated with quadriceps (p < 0.001, r = -0.500) fat pad edema.

Conclusions

Superolateral Hoffa and prefemoral fat pad edemas were associated with patellar maltracking parameters. Quadriceps fat pad edema and maltracking parameters were not associated. Superolateral Hoffa fat pad edema was positively correlated with prefemoral and negatively correlated with quadriceps fat pad edema.
How to successfully implement population health management: a scoping review
Authors: van Ede A. F. T. M. , Minderhout R. N. , Stein K. V. , Bruijnzeels M. A.
Published: August 2023

Background

Despite international examples, it is unclear for multisector initiatives which want to sustainably improve the health of a population how to implement Population Health Management (PHM) and where to start. Hence, the main purpose of this research is to explore current literature about the implementation of PHM and organising existing knowledge to better understand what needs to happen on which level to achieve which outcome.

Methods

A scoping review was performed within scientific literature. The data was structured using Context-Mechanism-Outcome, the Rainbow model of integrated care and six elements of PHM as theoretical concepts.

Results

The literature search generated 531 articles, of which 11 were included. Structuring the data according to these three concepts provided a framework that shows the skewed distribution of items that influence the implementation of PHM. It highlights that there is a clear focus on normative integration on the organisational level in ‘accountable regional organisation’. There is less focus on the normative integration of ‘cross domain business model’, ‘integrated data infrastructure’, and ‘population health data analytics’, and overall the perspective of citizen and professionals, indicating possible gaps of consideration.

Conclusions

A first step is taken towards a practical guide to implement PHM by illustrating the depth of the complexity and showing the partial interrelatedness of the items. Comparing the results with existing literature, the analysis showed certain gaps that are not addressed in practice, but should be according to other frameworks. If initiators follow the current path in literature, they may be missing out on some important components to achieve proper implementation of PHM.
Chronic remote ischemic conditioning treatment in patients with chronic stable angina (EARLY-MYO-CSA): a randomized, controlled proof-of-concept trial
Authors: Guo Quan , Zhao Zhenzhou , Yang Fan , Zhang Zhiwen , Rao Xiaoyu , Cui Jing , Shi Qingbo , Liu Kaiyuan , Zhao Kang , Tang Haiyu , Peng Liang , Ma Cao , Pu Jun , Li Muwei
Published: August 2023

Background

Chronic remote ischemic conditioning (CRIC) has been shown to improve myocardial ischemia in experimental animal studies; however, its effectiveness in patients with chronic stable angina (CSA) has not been investigated. We conducted a proof-of-concept study to investigate the efficacy and safety of a six-month CRIC treatment in patients with CSA.

Methods

The EARLY-MYO-CSA trial was a prospective, randomized, controlled trial evaluating the CRIC treatment in patients with CSA with persistent angina pectoris despite receiving ≥ 3-month guideline-recommended optimal medical therapy. The CRIC and control groups received CRIC (at 200 mmHg) or sham CRIC (at 60 mmHg) intervention for 6 months, respectively. The primary endpoint was the 6-month change of myocardial flow reserve (MFR) on single-photon emission computed tomography. The secondary endpoints were changes in rest and stress myocardial blood flow (MBF), angina severity according to the Canadian Cardiovascular Society (CCS) classification, the Seattle Angina Questionnaire (SAQ), and a 6-min walk test (6-MWT).

Results

Among 220 randomized CSA patients, 208 (105 in the CRIC group, and 103 in the control group) completed the treatment and endpoint assessments. The mean change in MFR was significantly greater in the CRIC group than in the control group (0.27 ± 0.38 vs. − 0.04 ± 0.25; P < 0.001). MFR increased from 1.33 ± 0.48 at baseline to 1.61 ± 0.53 (P < 0.001) in the CRIC group; however, a similar increase was not seen in the control group (1.35 ± 0.45 at baseline and 1.31 ± 0.44 at follow-up, P = 0.757). CRIC treatment, when compared with controls, demonstrated improvements in angina symptoms assessed by CCS classification (60.0% vs. 14.6%, P < 0.001), all SAQ dimensions scores (P < 0.001), and 6-MWT distances (440 [400–523] vs. 420 [330–475] m, P = 0.016). The incidence of major adverse cardiovascular events was similar between the groups.

Conclusions

CSA patients benefit from 6-month CRIC treatment with improvements in MFR, angina symptoms, and exercise performance. This treatment is well-tolerated and can be recommended for symptom relief in this clinical population.

Trial registration

[chictr.org.cn], identifier [ChiCTR2000038649].
Improving the cytotoxicity of immunotoxins by reducing the affinity of the antibody in acidic pH
Authors: Liu Xiaoyu , Tan Qingqing , Wen Jiaqi , Wang Xufei , Yang Gang , Li Yuxiao , Lu Ming , Ye Wei , Si Anfeng , Ma Sujuan , Ding Tong , Sun Luan , Liu Fang , Zhang Mei , Jiang Tao , Gao Wei
Published: August 2023

Background

Immunotoxins are antibody-toxin conjugates that bind to surface antigens and exert effective cytotoxic activity after internalization into tumor cells. Immunotoxins exhibit effective cytotoxicity and have been approved by the FDA to treat multiple hematological malignancies, such as hairy cell leukemia and cutaneous T-cell lymphoma. However, most of the internalized immunotoxin is degraded in lysosomes, and only approximately 5% of free toxin escapes into the cytosol to exert cytotoxicity. Many studies have improved immunotoxins by engineering the toxin fragment to reduce immunogenicity or increase stability, but how the antibody fragment contributes to the activity of immunotoxins has not been well demonstrated.

Methods

In the current study, we used 32A9 and 42A1, two anti-GPC3 antibodies with similar antigen-binding capabilities and internalization rates, to construct scFv-mPE24 immunotoxins and evaluated their in vitro and in vivo antitumor activities. Next, the antigen-binding capacity, trafficking, intracellular protein stability and release of free toxin of 32A9 scFv-mPE24 and 42A1 scFv-mPE24 were compared to elucidate their different antitumor activities. Furthermore, we used a lysosome inhibitor to evaluate the degradation behavior of 32A9 scFv-mPE24 and 42A1 scFv-mPE24. Finally, the antigen-binding patterns of 32A9 and 42A1 were compared under neutral and acidic pH conditions.

Results

Although 32A9 and 42A1 had similar antigen binding capacities and internalization rates, 32A9 scFv-mPE24 had superior antitumor activity compared to 42A1 scFv-mPE24. We found that 32A9 scFv-mPE24 exhibited faster degradation and drove efficient free toxin release compared to 42A1 scFv-mPE24. These phenomena were determined by the different degradation behaviors of 32A9 scFv-mPE24 and 42A1 scFv-mPE24 in lysosomes. Moreover, 32A9 was sensitive to the low-pH environment, which made the 32A9 conjugate easily lose antigen binding and undergo degradation in lysosomes, and the free toxin was then efficiently produced to exert cytotoxicity, whereas 42A1 was resistant to the acidic environment, which kept the 42A1 conjugate relatively stable in lysosomes and delayed the release of free toxin.

Conclusions

These results showed that a low pH-sensitive antibody-based immunotoxin degraded faster in lysosomes, caused effective free toxin release, and led to improved cytotoxicity compared to an immunotoxin based on a normal antibody. Our findings suggested that a low pH-sensitive antibody might have an advantage in the design of immunotoxins and other lysosomal degradation-dependent antibody conjugate drugs.
Single-cell RNA sequencing reveals small extracellular vesicles derived from malignant cells that contribute to angiogenesis in human breast cancers
Authors: Zhang Youxue , Zhen Fang , Sun Yue , Han Bing , Wang Hongyi , Zhang Yuhang , Zhang Huaixi , Hu Jing
Published: August 2023

Background

Breast cancer is the most common cancer affecting women across the world. Tumor endothelial cells (TECs) and malignant cells are the major constituents of the tumor microenvironment (TME), but their origin and role in shaping disease initiation, progression, and treatment responses remain unclear due to significant heterogeneity.

Methods

Tissue samples were collected from eight patients presenting with breast cancer. Single-cell RNA sequencing (scRNA-seq) analysis was employed to investigate the presence of distinct cell subsets in the tumor microenvironment. InferCNV was used to identify cancer cells. Pseudotime trajectory analysis revealed the dynamic process of breast cancer angiogenesis. We validated the function of small extracellular vesicles (sEVs)-derived protein phosphatase 1 regulatory inhibitor subunit 1B (PPP1R1B) in vitro experiments.

Results

We performed single-cell transcriptomics analysis of the factors associated with breast cancer angiogenesis and identified twelve subclusters of endothelial cells involved in the tumor microenvironment. We also identified the role of TECs in tumor angiogenesis and confirmed their participation in different stages of angiogenesis, including communication with other cell types via sEVs. Overall, the research uncovered the TECs heterogeneity and the expression levels of genes at different stages of tumor angiogenesis.

Conclusions

This study showed sEVs derived from breast cancer malignant cells promote blood vessel formation by activating endothelial cells through the transfer of PPP1R1B. This provides a new direction for the development of anti-angiogenic therapies for human breast cancer.
CX3CL1 promotes M1 macrophage polarization and osteoclast differentiation through NF-κB signaling pathway in ankylosing spondylitis in vitro
Authors: Feng Xinzhe , Zhu Shanbang , Qiao Junjie , Ji Zhou , Zhou Bole , Xu Weidong
Published: August 2023

Background

Ankylosing spondylitis (AS) is an autoimmune disease with a genetic correlation and is characterized by inflammation in the axial skeleton and sacroiliac joints. Many AS patients also have inflammatory bowel diseases (IBD), but the underlying causes of intestinal inflammation and osteoporosis in AS are not well understood. CX3CL1, a protein involved in inflammation, has been found to be up-regulated in AS patients and AS-model mice.

Methods

The authors investigated the effects of CX3CL1 on AS by studying its impact on macrophage polarization, inflammation factors, and osteoclast differentiation. Furthermore, the effects of inhibiting the NF-κB pathway and blocking CX3CL1 were assessed using BAY-117082 and anti-CX3CL1 mAb, respectively. AS model mice were used to evaluate the effects of anti-CX3CL1 mAb on limb thickness, spine rupture, and intestinal tissue damage.

Results

The authors found that CX3CL1 increased the expression of M1-type macrophage markers and inflammation factors, and promoted osteoclast differentiation. This effect was mediated through the NF-κB signaling pathway. Inhibition of the NF-κB pathway prevented M1-type macrophage polarization, reduced inflammation levels, and inhibited osteoclast differentiation. Injection of anti-CX3CL1 mAb alleviated limb thickness, spine rupture, and intestinal tissue damage in AS model mice by inhibiting M1-type macrophage polarization and reducing intestinal tissue inflammation.

Conclusions

The study demonstrated that up-regulated CX3CL1 promotes M1-type macrophage polarization and osteoclast differentiation through the NF-κB signaling pathway. Inhibition of this pathway and blocking CX3CL1 can alleviate inflammation and bone destruction in AS. These findings contribute to a better understanding of the pathogenesis of AS and provide a basis for clinical diagnosis and treatment.