bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Atypical Dopamine Transporter Inhibitor CE-158 Enhances Dopamine Neurotransmission in the Prefrontal Cortex of Male Rats: A Behavioral, Electrophysiological, and Microdialysis Study
Authors: Sagheddu Claudia , Cancedda Enzo , Bagheri Farshid , Kalaba Predrag , Muntoni Anna Lisa , Lubec Jana , Lubec Gert , Sanna Fabrizio , Pistis Marco 
Published: September 2023

Abstract

Background
Dopamine plays a key role in several physiological functions such as motor control, learning and memory, and motivation and reward. The atypical dopamine transporter inhibitor S,S stereoisomer of 5-(((S)-((S)-(3-bromophenyl)(phenyl)methyl)sulfinyl)methyl)thiazole (CE-158) has been recently reported to promote behavioral flexibility and restore learning and memory in aged rats.

Methods
Adult male rats were i.p. administered for 1 or 10 days with CE-158 at the dose of 1 or 10 mg/kg and tested for extracellular dopamine in the medial prefrontal cortex by means of intracerebral microdialysis and single unit cell recording in the same brain area. Moreover, the effects of acute and chronic CE-158 on exploratory behavior, locomotor activity, prepulse inhibition, working memory, and behavioral flexibility were also investigated.

Results
CE-158 dose-dependently potentiated dopamine neurotransmission in the medial prefrontal cortex as assessed by intracerebral microdialysis. Moreover, repeated exposure to CE-158 at 1 mg/kg was sufficient to increase the number of active pyramidal neurons and their firing frequency in the same brain area. In addition, CE-158 at the dose of 10 mg/kg stimulates exploratory behavior to the same extent after acute or chronic treatment. Noteworthy, the chronic treatment at both doses did not induce any behavioral alterations suggestive of abuse potential (e.g., motor behavioral sensitization) or pro–psychotic-like effects such as disruption of sensorimotor gating or impairments in working memory and behavioral flexibility as measured by prepulse inhibition and Y maze.

Conclusions
Altogether, these findings confirm CE-158 as a promising pro-cognitive agent and contribute to assessing its preclinical safety profile in a chronic administration regimen for further translational testing.
Improving model transferability for clinical note section classification models using continued pretraining
Authors: Zhou Weipeng , Yetisgen Meliha , Afshar Majid , Gao Yanjun , Savova Guergana , Miller Timothy A 
Published: September 2023

Abstract

Objective
The classification of clinical note sections is a critical step before doing more fine-grained natural language processing tasks such as social determinants of health extraction and temporal information extraction. Often, clinical note section classification models that achieve high accuracy for 1 institution experience a large drop of accuracy when transferred to another institution. The objective of this study is to develop methods that classify clinical note sections under the SOAP (“Subjective,” “Object,” “Assessment,” and “Plan”) framework with improved transferability.

Materials and methods
We trained the baseline models by fine-tuning BERT-based models, and enhanced their transferability with continued pretraining, including domain-adaptive pretraining and task-adaptive pretraining. We added in-domain annotated samples during fine-tuning and observed model performance over a varying number of annotated sample size. Finally, we quantified the impact of continued pretraining in equivalence of the number of in-domain annotated samples added.

Results
We found continued pretraining improved models only when combined with in-domain annotated samples, improving the F1 score from 0.756 to 0.808, averaged across 3 datasets. This improvement was equivalent to adding 35 in-domain annotated samples.

Discussion
Although considered a straightforward task when performing in-domain, section classification is still a considerably difficult task when performing cross-domain, even using highly sophisticated neural network-based methods.

Conclusion
Continued pretraining improved model transferability for cross-domain clinical note section classification in the presence of a small amount of in-domain labeled samples.
Quantitative analysis of MGMT promoter methylation in glioblastoma suggests nonlinear prognostic effect
Authors: Gibson David , Ravi Akshay , Rodriguez Eduardo , Chang Susan , Oberheim Bush Nancy , Taylor Jennie , Clarke Jennifer , Solomon David , Scheffler Aaron , Witte John , Lambing Hannah , Okada Hideho , Berger Mitchel , Chehab Farid , Butowski Nicholas A 
Published: September 2023

Abstract

Background
Epigenetic inhibition of the O6-methylguanine-DNA-methyltransferase (MGMT) gene has emerged as a clinically relevant prognostic marker in glioblastoma (GBM). Methylation of the MGMT promoter has been shown to increase chemotherapy efficacy. While traditionally reported as a binary marker, recent methodological advancements have led to quantitative methods of measuring promoter methylation, providing clearer insight into its functional relationship with survival.

Methods
A CLIA assay and bisulfite sequencing was utilized to develop a quantitative, 17-point, MGMT promoter methylation index. GBMs of 240 newly diagnosed patients were sequenced and risk for mortality was assessed. Nonlinearities were captured by fitting splines to Cox proportional hazard models and plotting smoothed residuals. Covariates included age, Karnofsky performance status, IDH1 mutation, and extent of resection.

Results
Median follow-up time and progression-free survival were 16 and 9 months, respectively. A total of 176 subjects experienced death. A one-unit increase in promoter CpG methylation resulted in a 4% reduction in hazard (95% CI 0.93–0.99, P &lt; .005). GBM patients with low levels of promoter methylation (1-6 CpG sites) fared markedly worse (HR = 1.62, 95% CI 1.03–2.54, P &lt; .036) than individuals who were unmethylated. Subjects with medium levels of promoter methylation (7–12 sites) had the greatest reduction in hazard (HR = 0.48, 95% CI 0.29–0.80, P &lt; .004), followed by individuals in the highest promoter methylation tertile (HR = 0.62, 95% CI 0.40–0.97, P &lt; .035).

Conclusions
Our findings suggest that the relationship between the extent of MGMT promoter methylation and survival in GBM may be nonlinear. These findings challenge the current understanding of MGMT and underlines the clinical importance of determining its prognostic utility. Potential limitations include censoring, sample size, and extraneous mutations.
How does Mei-yu precipitation respond to climate change?
Authors: Sun Bo , Xue Rufan , Li Wanling , Zhou Siyu , Li Huixin , Zhou Botao , Wang Huijun 
Published: September 2023

ABSTRACT
Mei-yu is an important weather phenomenon in the middle-lower Yangtze River valley (YRV) region. This study investigates the changes in the characteristics of Mei-yu under global warming and the potential reasons based on observation and reanalysis data during 1961–2022. Notable increasing long-term trends are detected in the number of days without rainfall (NDWOR), the intensity of rainfall events, and the frequency and intensity of extreme precipitation events (EPEs) in the YRV region during the Mei-yu period (15 June–10 July) over past decades. The increasing trend in NDWOR is attributed to decreased relative humidity over land surface and a longer time for the air to be replenished with moisture after rainfall events in a warming climate. The increasing trends in the intensity of rainfall events and frequency/intensity of EPEs are attributed to the strengthened transient water vapor convergence and convection in the atmosphere under global warming. Furthermore, the response of Mei-yu to 2°C of global warming with respect to the pre-industrial climate is analysed using CMIP6 models. The results suggest that the NDWOR, intensity of rainfall events and frequency of EPEs will increase in the YRV region during the Mei-yu period under the 2°C warming scenario, which implies a more challenging climate risk management in the future. Overall, the intensity of rainfall events during the Mei-yu period has the most significant response to climate change in observations and projections. The model results have a relatively large uncertainty.
Baseline Cytomegalovirus Viremia at Cryptococcal Meningitis Diagnosis Is Associated With Long-term Increased Incident TB Disease and Mortality in a Prospective Cohort of Ugandan Adults With HIV
Authors: Ellis Jayne , Bangdiwala Ananta S , Skipper Caleb P , Tugume Lillian , Nsangi Laura , Matovu John , Pastick Katelyn A , Ssebambulidde Kenneth , Morawski Bozena M , Musubire Abdu K , Schleiss Mark R , Moore David A J , Jarvis Joseph N , Boulware David R , Meya David B , Castelnuovo Barbara 
Published: September 2023

Abstract

Background
Adults with HIV-associated cryptococcal meningitis have overlapping burdens of cytomegalovirus (CMV) and tuberculosis (TB) coinfections. CMV infection/reactivation is strongly associated with CMV-specific memory T-cell activation and upregulation of type 1 interferons, which may lead to increased risk of TB disease and poor outcomes.

Methods
We conducted a cohort study of 2-week survivors of cryptococcal meningitis during 2010–2021 to determine TB incidence and all-cause mortality over time stratified by baseline CMV status.

Results
We followed 497 Ugandans with HIV-associated cryptococcal meningitis for a median (interquartile range) of 4.6 (2.6–53.9) months. Overall, 42% (210/497) developed incident TB disease or died. One-fifth (98/497, 19.7%) developed incident TB disease, and 29% (142/497) of participants died during follow-up. Of 259 participants with CMV viral load measured at baseline, 37% (96/259) had concurrent CMV viremia (defined as anyone with detectable CMV DNA in plasma/serum by qualitative polymerase chain reaction [PCR] detection). Of 59 with measured CMV immunoglobulin G (IgG), 100% had positive CMV IgG antibody serology (≥10 enzyme-linked immunosorbent assay units/mL). CMV viremia was positively associated with higher HIV viral load (196 667 vs 73 295 copies/mL; P = .002) and higher cerebrospinal fluid fungal burden (68 500 vs 14 000 cfu/mL; P = .002) compared with those without. Participants with high-level CMV viremia (defined as CMV viral load ≥1000 IU/mL) had twice the risk of incident TB (subdistribution adjusted hazard ratio [aHR], 2.18; 95% CI, 1.11–4.27) and death (aHR, 1.99; 95% CI, 1.14–3.49) compared with participants with no or low-level CMV viremia. There was no association between the CMV IgG index and the incidence of TB/death (P = .75).

Conclusions
CMV viremia &gt;1000 IU/mL at meningitis diagnosis was associated with increased incident TB disease and mortality during long-term follow-up. Future studies to determine the causal relationship and potential for therapeutic intervention are warranted.
Twenty-Year Follow-Up of a Phase II Trial of Taxotere/Carboplatin/Herceptin in Patients With Metastatic HER2-Positive Breast Cancer
Authors: Gomez Marti Juan Luis , Nasrazadani Azadeh , Ding Ying , Normolle Daniel , Brufsky Adam M 
Published: September 2023

Abstract

Background
As the implementation of trastuzumab, several studies have investigated new agents and regimens to treat human epidermal growth factor 2-positive (HER2+) metastatic breast cancer (MBC). However, long-term survival analyses from HER2-targeted therapies are lacking. This is a 20-year follow-up study of a phase II trial that evaluated the activity and safety of docetaxel in combination with carboplatin and trastuzumab (TCH) in patients with HER2+ MBC.

Materials and Methods
This is a follow-up of a phase II, single-arm, open-label study. The primary objective was the activity from the combination of TCH in terms of response rate (RR). Secondary objectives included the activity from TCH in terms of response duration (RD), time to progression (TTP), overall survival (OS), and percent one-year survival.

Results
Between 11/1999 and 10/2002, 40 women were enrolled. Most patients (67.5%) had visceral metastasis on enrollment. After 2 decades and 3 months from first enrollment, there were 4 (10%) survivors (median follow-up of 3.2 years). The RR for complete response (CR) or partial response (PR) was 72.5%. The RR for CR was 42.5%. RD was 8 months. Median TTP was 10.8 months. Participants achieved a median OS of 39.8 months. Percent one-year survival was 92.5%.

Conclusion
A subset of patients (10%) receiving trastuzumab in the metastatic setting have achieved long-term survival beyond 20 years.
Severe acute respiratory syndrome coronavirus 2 infection leads to Tau pathological signature in neurons
Authors: Di Primio Cristina , Quaranta Paola , Mignanelli Marianna , Siano Giacomo , Bimbati Matteo , Scarlatti Arianna , Piazza Carmen Rita , Spezia Piero Giorgio , Perrera Paola , Basolo Fulvio , Poma Anello Marcello , Costa Mario , Pistello Mauro , Cattaneo Antonino 
Published: September 2023

Abstract
COVID-19 has represented an issue for global health since its outbreak in March 2020. It is now evident that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in a wide range of long-term neurological symptoms and is worryingly associated with the aggravation of Alzheimer’s disease. Little is known about the molecular basis of these manifestations. Here, several strain variants were used to infect SH-SY5Y neuroblastoma cells and K18-hACE C57BL/6J mice. The Tau phosphorylation profile and aggregation propensity upon infection were investigated on cellular extracts, subcellular fractions, and brain tissue. The viral proteins spike, nucleocapsid, and membrane were overexpressed in SH-SY5Y cells, and the direct interaction and effect on Tau phosphorylation were checked using immunoblot experiments. Upon infection, Tau is phosphorylated at several pathological epitopes associated with Alzheimer’s disease and other tauopathies. Moreover, this event increases Tau’s propensity to form insoluble aggregates and alters its subcellular localization. Our data support the hypothesis that SARS-CoV-2 infection in the central nervous system triggers downstream effects altering Tau function, eventually leading to the impairment of neuronal function.
Addressing Social Desirability Bias When Measuring Child Labor Use: An Application to Cocoa Farms in Côte d’Ivoire
Authors: Jouvin Marine 
Published: September 2023

Abstract
This paper proposes new estimates of child labor use in Côte d’Ivoire’s cocoa farms that are certified free of child labor. The study relies on list experiments (LE) to overcome social desirability bias associated with measuring sensitive issues, implemented on a sample of 4,458 Ivorian cocoa farmers. Findings show that 24 percent of them were helped by at least one child under 16 for harvesting and breaking the cocoa pods during the past 12 months, 21 percent for preparing their farm, and 25 percent employed and paid at least one child to perform any task on their cocoa farm. These results are twice as high as those declared by farmers when directly questioning them about their child labor use. This study provides evidence that the LE method, while more cognitively demanding than the direct questioning method, can be successfully understood by populations with low levels of education. Findings further show that, in this setting, the LE estimates are robust to specific LE design changes.
Big Assumptions in Online and Blended Continuing Professional Development: Finding Our Way Forward Together
Authors: Bernson-Leung Miya E. , MacNeill Heather 
Published: September 2023

Abstract:
Continuing professional development (CPD) providers and faculty face a practice gap between our knowledge of effective practices in CPD and our implementation of them, particularly in online environments. Developmental psychologists Bob Kegan and Lisa Lahey have attributed such knowledge-implementation gaps to an “Immunity to Change” rooted in tacit “Big Assumptions.” These Big Assumptions produce fears or worries, reveal competing commitments, and result in actions or inactions that hinder intended change. We sought to understand the barriers to change in online and blended CPD, to support CPD leaders in pursuing their goals for optimal use of technology in CPD. This inquiry arose from the 13th National Continuing Professional Development Accreditation Conference of the Royal College of Physicians and Surgeons of Canada and the College of Family Physicians of Canada, a virtual conference held in October 2022. After introducing the Immunity to Change framework and best practices in online and blended learning, we invited audience members to list Big Assumptions in CPD through chat and polling software. These responses were analyzed and grouped into five interrelated Big Assumptions that suggest a number of key barriers to optimal implementation of online CPD. We present data that counter each Big Assumption along with practical approaches to facilitate desired change for CPD.
Secondary Breast Angiosarcoma After a Primary Diagnosis of Breast Cancer
Authors: Chau Bonny , Loggers Elizabeth T. , Cranmer Lee D. , Mogal Harveshp , Sharib Jeremy M. , Kim Edward Y. , Schaub Stephanie K. , Paulson Kelly G. , Linden Hannah M. , Specht Jennifer M. , Kim Janice N. , Javid Sara H. , Wagner Michael J. 
Published: September 2023

Objectives:
Angiosarcoma is a rare complication of breast-conserving therapy. This study evaluated the change in incidence between 1992 and 2016 of secondary breast angiosarcoma (SBA) in patients with a history of breast cancer and the impact of management strategies for the original breast carcinoma on angiosarcoma treatment.

Methods:
Breast cancer and angiosarcoma cases were abstracted from the Surveillance, Epidemiology, and End Result (SEER) database. SBAs were defined as angiosarcomas located in the breast occurring after a prior breast cancer diagnosis. Primary breast angiosarcomas (PBAs) were defined as an angiosarcoma diagnosis listed as “one primary only.” Incidence rates were estimated using a proportion of the US total population. Survival was analyzed by the Kaplan-Meier method, and Cox proportional hazard models were used to assess the association of clinicopathologic characteristics on overall survival.

Results:
Between 1992 and 2016, 193 cases of SBA were reported in the SEER dataset in patients with a prior history of breast cancer. The incidence of breast angiosarcoma in patients with a prior diagnosis of breast cancer increased 3-fold from about 10 cases per 100,000 person-years to about 30 cases per 100,000 person-years over this same period (P=0.0037). For treatment of SBA (n=193), almost all (95%) had surgery. Nine percent received radiation (compared with 35% of patients with PBA, P<0.001) and 23% received chemotherapy (vs. 45% for PBA, P=0.11).

Conclusions:
We demonstrate an increasing incidence of SBA over the study period. These data can help inform shared decision-making for optimal management of locoregional breast cancer and raise awareness of secondary angiosarcoma.
MicroNAPS: A Novel Classification for Infants with Micrognathia, Robin Sequence, and Tongue-based Airway Obstruction
Authors: Resnick Cory M. , Katz Eliot , Varidel Alistair 
Published: September 2023

Background:
Robin sequence (RS) describes a heterogeneous population with micrognathia, glossoptosis, and upper airway obstruction (UAO). Workup, treatment, outcomes assessment, and research inclusion are widely variable. Despite several classifications and algorithms, none is broadly endorsed. The objective of this investigation was to develop and trial a novel classification system designed to enhance clinical communication, treatment planning, prognostication, and research.

Methods:
This is a retrospective cross-sectional study. A classification system was developed with five elements: micrognathia, nutrition, airway, palate, syndrome/comorbidities (MicroNAPS). Definitions and a framework for “stage” assignment (R0–R4) were constructed. Stage “tongue-based airway obstruction” (TBAO) was defined for infants with glossoptosis and UAO without micrognathia. MicroNAPS was applied to 100 infants with at least 1-year follow-up. Clinical course, treatment, airway, and feeding characteristics were assessed. Descriptive and analytic statistics were calculated and a P value less than 0.05 was considered significant.

Results:
Of the 100 infants, 53 were male. Mean follow-up was 5.0 ± 3.6 years. R1 demonstrated feeding-predominant mild RS for which UAO was managed nonoperatively but gastrostomy tubes were prevalent. R2 was characterized by airway-predominant moderate RS, typically managed with mandibular distraction or tongue-lip adhesion, with few gastrostomy tubes and short lengths-of-stay. R3 denoted severe RS, with similar UAO treatment to R2, but with more surgical feeding tubes and longer admissions. R4 represented a complex phenotype with 33% tracheostomies, protracted hospitalizations, and delayed palatoplasty. R0 (“at risk”) and TBAO groups displayed the most variability.

Conclusions:
MicroNAPS is easy to use and associated with relevant disease characteristics. We propose its adoption in clinical and research settings.
Salt intake, blood pressure and cardiovascular disease mortality in England, 2003–2018
Authors: Song Jing , Tan Monique , Wang Changqiong , Brown Mhairi K. , Pombo-Rodrigues Sonia , MacGregor Graham A. , He Feng J. 
Published: September 2023

Objectives:
The aim of this study was to assess the changes in salt intake and concomitant changes in blood pressure (BP) and cardiovascular disease (CVD) mortality in England from 2003 to 2018.

Methods:
National surveys and death registration data were used for the analysis of salt intake as measured by 24-h urinary sodium excretion (449–1069 participants per year), BP (2651–6738 participants per year) and CVD mortality.

Results:
A decline in salt intake from 9.38 (SD 4.64) to 7.58 (3.41) g/d was observed between 2003 and 2014 (P < 0.01), followed by an increase to 8.39 (4.13) g/d in 2018 (P < 0.01). Similar trends in BP and CVD mortality were also observed between 2003 and 2018. SBP/DBP decreased from 125.3 (15.92)/74.48 (11.33) mmHg to 122.57 (14.92)/73.33 (10.75) mmHg between 2003 and 2014 (P < 0.01), followed by a plateau up to 2018 [122.04 (14.64)/73.84 (10.54) mmHg, P > 0.05]. Likewise, a fall in stroke and ischaemic heart disease mortality rates was observed between 2003 and 2014, from 12.24 and 43.44 cases per 100 000, to 8.19 and 27.23 cases per 100 000 (P < 0.01), respectively, followed by a plateau afterwards (P > 0.05).

Conclusion:
The UK salt reduction programme was initially successful in reducing population salt intake by 19% (from 9.38 g/d in 2003 to 7.58 g/d in 2014). However, in recent years, the programme stalled and thus led to an interruption in the decline of salt intake. BP and CVD mortality reduction was also interrupted when salt reduction stalled. The changes in salt intake may have played an important role in the concomitant changes in BP and CVD mortality. Urgent action is needed to reinvigorate the UK's once world-leading salt reduction programme.