bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating primary care networks in low-income and lower middle-income countries: a scoping review
Authors: Agyemang-Benneh Adwoa , Francetic Igor , Hammond Jonathan , Checkland Katherine 
Published: August 2023

IntroductionPrimary care networks (PCNs) are claimed to be an effective model to organise and deliver primary healthcare through collaborative relationships and effective coordination of primary care activities. Though increasingly implemented in different contexts, there is limited evidence on the effectiveness of PCNs in low-income and lower middle-income countries (LLMICs).ObjectiveOur scoping review aims to understand how PCNs in LLMICs have been conceptualised, implemented and analysed in the literature and further explores the evidence of the effectiveness of these networks.MethodsWe structured our review using Arksey and O’Malley’s framework for scoping reviews and recommendations by Levacet al. We also used the population, concept and context (PCC) guide of the Joanna Briggs Institute (JBI) methodology for scoping reviews to define the search strategy. The identified documents were then mapped, using Cunningham’s evaluation framework for health networks, to understand how PCNs are conceived in LLMIC settings.ResultsWe identified 20 documents describing PCNs in five LLMICs. The selected documents showed differing forms and complexities of networks, with a majority resourced by government, non-governmental and donor entities. Most networks were mandated, and established with defined goals, although these were not always understood by stakeholders. Unlike PCNs in developed settings, the scoping review did not identify integration of care as a major goal for the establishment of PCNs in LLMICs. Network evaluation relationships, outputs and outcomes also varied across the five networks in the identified documents, and perceptions of effectiveness differed across stakeholder groups.ConclusionPCNs in LLMICs benefit from clearly stated goals and measurable outcomes, which facilitates evaluation. In order to maximise the benefits, careful attention to the aspects of network design and operation is required. Future research work could shed light on some of the missing pieces of evidence on their effectiveness by, for example, considering differential consequences of modes of network establishment and operation, including unintended consequences in the systems within which they reside, and evaluating long-term implications.
Multivariate analysis of refractive state in eyes with keratoconus
Authors: Chetty Elizabeth 
Published: August 2023

ObjectiveTo demonstrate a multivariate method of analysis of the short-term variation of refractive state in keratoconus (KC) patients.Methods and analysisIn this observational study, 19 eyes with KC and 19 healthy control eyes were measured. The study included both male and female participants and the mean age was 23.6 years (range 18–34 years) and 23.2 years (range 22–26 years) for KC and control participants, respectively. Forty consecutive autorefractor measurements were taken for each participant and the short-term variation thereof was analysed using multivariate methods of analysis.Results and conclusionShort-term variation of refractive state is greater in eyes with KC than in healthy control eyes and variation increases with severity of disease. A novel finding was that there was much more ortho-astigmatic and oblique-astigmatic variation seen in KC eyes than in control eyes which had predominately stigmatic variation. Refractive state is described by three components, namely, sphere, cylinder and axis. Although it is multivariate in nature, it is often analysed using univariate statistical methods. In diseases such as KC, where early diagnosis is crucial for a good prognosis, it is necessary that researchers endeavour to investigate the disease from different perspectives to fully understand the nature of the disease. This paper comprehensively demonstrates the multivariate statistical methods of analysis of refractive data. The implementation of this analysis provides insight into the short-term variation of refractive data in healthy and keratoconic eyes, and these findings have not been demonstrated before using univariate statistics.
Effect of a targeted quality improvement education on opioid prescribing
Authors: Kaley Amanda , Brenner Jay M , Prince Anna M , Wojcik Susan M 
Published: August 2023

BackgroundThe opioid epidemic is a serious social, economic and public health problem. This study was designed to evaluate the effectiveness of individual institutional opioid prescriber training on prescriber adherence to the Centers for Disease Control and Prevention (CDC’s) guidelines for responsible opioid prescribing practices to treat acute pain.MethodsOpioid prescribing data were collected from an academic medical centre and its associated outpatient clinics. A baseline for opioid prescribing practices was collected for 2 years and 2 months prior to the planned intervention. Departments responsible for 5% or more of the total institutional opioid prescriptions were chosen to study in detail. A number of opioid prescriptions per department per day and their compliance with the maximum daily dose (MDD) recommendations put out by the CDC were determined.InterventionThe hospital administration implemented a mandatory opioid prescriber training as part of their standard annual provider education for all medical staff, who were all required to attest having read it and pass a quiz by 30 September 2019, which was chosen as the end date for the pre-intervention data. Data were analysed preintervention and postintervention to assess the effect of this intervention on opioid prescribing.ResultsOverall opioid prescribing rates decreased by 18.3% and there were significant decreases in opioid prescribing rate in five out of the seven departments/divisions. Overall, there was a statistically significant decrease in the compliance with MDD before (71.3%) and after (67.3%) the intervention (4%, 95% CI 3.13% to 4.87% difference, p<0.001). Additionally, there were statistically significant increases in compliance with CDC guidelines in three departments/divisions. However, there was a statistically significant decrease in compliance with CDC guidelines after intervention in two departments.ConclusionsThe results of this study were largely encouraging for the effectiveness of this institutional mandatory prescriber training.
T-cell tolerant fraction as a predictor of immune-related adverse events
Authors: Ostmeyer Jared , Park Jason Y , von Itzstein Mitchell S , Hsiehchen David , Fattah Farjana , Gwin Mary , Catalan Rodrigo , Khan Shaheen , Raj Prithvi , Wakeland Edward K , Xie Yang , Gerber David E 
Published: August 2023

BackgroundImmune checkpoint inhibitor (ICI) therapies may cause unpredictable and potentially severe autoimmune toxicities termed immune-related adverse events (irAEs). Because T cells mediate ICI effects, T cell profiling may provide insight into the risk of irAEs. Here we evaluate a novel metric—the T-cell tolerant fraction—as a predictor of future irAEs.MethodsWe examined T-cell receptor beta (TRB) locus sequencing from baseline pretreatment samples from an institutional registry and previously published studies. For each patient, we used TRB sequences to calculate the T-cell tolerant fraction, which was then assessed as a predictor of future irAEs (classified as Common Terminology Criteria for Adverse Event grade 0–1 vs grade ≥2). We then compared the tolerant fraction to TRB clonality and diversity. Finally, the tolerant fraction was assessed on (1) T cells enriched against napsin A, a potential autoantigen of irAEs; (2) thymic versus peripheral blood T cells; and (3) TRBs specific for various infections and autoimmune diseases.ResultsA total of 77 patients with cancer (22 from an institutional registry and 55 from published studies) receiving ICI therapy (43 CTLA4, 19 PD1/PDL1, 15 combination CTLA4+PD1/PDL1) were included in the study. The tolerant fraction was significantly lower in cases with clinically significant irAEs (p<0.001) and had an area under the receiver operating curve (AUC) of 0.79. The tolerant fraction was lower for each ICI treatment category, reaching statistical significance for CTLA4 (p<0.001) and demonstrating non-significant trends for PD1/PDL1 (p=0.21) and combination ICI (p=0.18). The tolerant fraction for T cells enriched against napsin A was lower than other samples. The tolerant fraction was also lower in thymic versus peripheral blood samples, and lower in some (multiple sclerosis) but not other (type 1 diabetes) autoimmune diseases. In our study cohort, TRB clonality had an AUC of 0.62, and TRB diversity had an AUC of 0.60 for predicting irAEs.ConclusionsAmong patients receiving ICI, the baseline T-cell tolerant fraction may serve as a predictor of clinically significant irAEs.
Further delineation of the rare GDACCF (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies syndrome): genotype and phenotype of 22 patients withZNF148mutations
Authors: Szakszon Katalin , Lourenco Charles Marques , Callewaert Bert Louis , Geneviève David , Rouxel Flavien , Morin Denis , Denommé-Pichon Anne-Sophie , Vitobello Antonio , Patterson Wesley G , Louie Raymond , Pinto e Vairo Filippo , Klee Eric , Kaiwar Charu , Gavrilova Ralitza H , Agre Katherine E , Jacquemont Sebastien , Khadijé Jizi , Giltay Jacques , van Gassen Koen , Merő Gabriella , Gerkes Erica , Van Bon Bregje W , Rinne Tuula , Pfundt Rolph , Brunner Han G , Caluseriu Oana , Grasshoff Ute , Kehrer Martin , Haack Tobias B , Khelifa Melik Malek , Bergmann Anke Katharina , Cueto-González Anna Maria , Martorell Ariadna Campos , Ramachandrappa Shwetha , Sawyer Lindsey B , Fasel Pascale , Braun Dominique , Isis Atallah , Superti-Furga Andrea , McNiven Vanda , Chitayat David , Ahmed Syed Anas , Brennenstuhl Heiko , Schwaibolf Eva MC , Battisti Gladys , Parmentier Benoit , Stevens Servi J C 
Published: August 2023

BackgroundPathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in theZNF148gene causing GDACCF syndrome (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies; MIM #617260) have been reported in five individuals so far.MethodsAs a result of an international collaboration using GeneMatcher Phenome Central Repository and personal communications, here we describe the clinical and molecular genetic characteristics of 22 previously unreported individuals.ResultsThe core clinical phenotype is characterised by developmental delay particularly in the domain of speech development, postnatal growth retardation, microcephaly and facial dysmorphism. Corpus callosum abnormalities appear less frequently than suggested by previous observations. The identified mutations concerned nonsense or frameshift variants that were mainly located in the last exon of theZNF148gene. Heterozygous deletion including the entireZNF148gene was found in only one case. Most mutations occurred de novo, but were inherited from an affected parent in two families.ConclusionThe GDACCF syndrome is clinically diverse, and a genotype-first approach, that is, exome sequencing is recommended for establishing a genetic diagnosis rather than a phenotype-first approach. However, the syndrome may be suspected based on some recurrent, recognisable features. Corpus callosum anomalies were not as constant as previously suggested, we therefore recommend to replace the term ‘GDACCF syndrome’ with ‘ZNF148-related neurodevelopmental disorder’.
Parkin Deficiency Suppresses Antigen Presentation to Promote Tumor Immune Evasion and Immunotherapy Resistance
Authors: Perales-Linares Renzo , Leli Nektaria Maria , Mohei Hesham , Beghi Silvia , Rivera Osvaldo D. , Kostopoulos Nektarios , Giglio Andrea , George Subin S. , Uribe-Herranz Mireia , Costabile Francesca , Pierini Stefano , Pustylnikov Sergei , Skoufos Giorgos , Barash Yoseph , Hatzigeorgiou Artemis G. , Koumenis Constantinos , Maity Amit , Lotze Michael T. , Facciabene Andrea 
Published: August 2023

Abstract

Parkin is an E3 ubiquitin ligase, which plays a key role in the development of Parkinson disease. Parkin defects also occur in numerous cancers, and a growing body of evidence indicates that Parkin functions as a tumor suppressor that impedes a number of cellular processes involved in tumorigenesis. Here, we generated murine and human models that closely mimic the advanced-stage tumors where Parkin deficiencies are found to provide deeper insights into the tumor suppressive functions of Parkin. Loss of Parkin expression led to aggressive tumor growth, which was associated with poor tumor antigen presentation and limited antitumor CD8+ T-cell infiltration and activation. The effect of Parkin deficiency on tumor growth was lost following depletion of CD8+ T cells. In line with previous findings, Parkin deficiency was linked with mitochondria-associated metabolic stress, PTEN degradation, and enhanced Akt activation. Increased Akt signaling led to dysregulation of antigen presentation, and treatment with the Akt inhibitor MK2206-2HCl restored antigen presentation in Parkin-deficient tumors. Analysis of data from patients with clear cell renal cell carcinoma indicated that Parkin expression was downregulated in tumors and that low expression correlated with reduced overall survival. Furthermore, low Parkin expression correlated with reduced patient response to immunotherapy. Overall, these results identify a role for Parkin deficiency in promoting tumor immune evasion that may explain the poor prognosis associated with loss of Parkin across multiple types of cancer.

Significance:
Parkin prevents immune evasion by regulating tumor antigen processing and presentation through the PTEN/Akt network, which has important implications for immunotherapy treatments in patients with Parkin-deficient tumors.
Data from Resistance to Selective FGFR Inhibitors in <i>FGFR-</i>Driven Urothelial Cancer
Authors: Facchinetti Francesco , Hollebecque Antoine , Braye Floriane , Vasseur Damien , Pradat Yoann , Bahleda Rastislav , Pobel Cédric , Bigot Ludovic , Déas Olivier , Florez Arango Juan David , Guaitoli Giorgia , Mizuta Hayato , Combarel David , Tselikas Lambros , Michiels Stefan , Nikolaev Sergey I. , Scoazec Jean-Yves , Ponce-Aix Santiago , Besse Benjamin , Olaussen Ken A. , Loriot Yohann , Friboulet Luc 
Published: August 2023

<div>Abstract<p>Several fibroblast growth factor receptor (FGFR) inhibitors are approved or in clinical development for the treatment of <i>FGFR</i>-driven urothelial cancer, and molecular mechanisms of resistance leading to patient relapses have not been fully explored. We identified 21 patients with <i>FGFR</i>-driven urothelial cancer treated with selective FGFR inhibitors and analyzed postprogression tissue and/or circulating tumor DNA (ctDNA). We detected single mutations in the FGFR tyrosine kinase domain in seven (33%) patients (FGFR3 N540K, V553L/M, V555L/M, E587Q; FGFR2 L551F) and multiple mutations in one (5%) case (FGFR3 N540K, V555L, and L608V). Using Ba/F3 cells, we defined their spectrum of resistance/sensitivity to multiple selective FGFR inhibitors. Eleven (52%) patients harbored alterations in the PI3K–mTOR pathway (<i>n</i> = 4 <i>TSC1/2</i>, <i>n</i> = 4 <i>PIK3CA</i>, <i>n</i> = 1 <i>TSC1</i> and <i>PIK3CA</i>, <i>n</i> = 1 <i>NF2</i>, <i>n</i> = 1 <i>PTEN</i>). In patient-derived models, erdafitinib was synergistic with pictilisib in the presence of PIK3CA E545K, whereas erdafitinib–gefitinib combination was able to overcome bypass resistance mediated by EGFR activation.</p>Significance:<p>In the largest study on the topic thus far, we detected a high frequency of FGFR kinase domain mutations responsible for resistance to FGFR inhibitors in urothelial cancer. Off-target resistance mechanisms involved primarily the PI3K–mTOR pathway. Our findings provide preclinical evidence sustaining combinatorial treatment strategies to overcome bypass resistance.</p></div>
Dynamics of High-Density Unipolar Epicardial Electrograms During PFA
Authors: Amorós-Figueras Gerard , Casabella-Ramon Sergi , Moreno-Weidmann Zoraida , Ivorra Antoni , Guerra Jose M. , García-Sánchez Tomás 
Published: August 2023

BACKGROUND:
Pulsed field ablation (PFA) is a novel nonthermal cardiac ablation technology based on irreversible electroporation (IRE). While areas of IRE lead to durable lesions, the surrounding regions, where reversible electroporation occurs, recover. The behavior of local electrograms in areas of different electroporation levels remains unknown. The goal of this study is to characterize electrogram dynamics after PFA in IRE and reversible electroporation areas.

METHODS:
A total of 6 domestic swine were used. PFA was applied in the epicardium of the right and left ventricles using a focal monopolar catheter. Additional radiofrequency ablations were performed. Epicardial unipolar electrograms were acquired at baseline and for 60 minutes post PFA/radiofrequency ablation using a high-density electrode matrix attached to the epicardium. Electrogram dynamics were analyzed in areas corresponding to different levels of electroporation. Acute lesion formation was assessed after 3 to 5 hours by triphenyl tetrazolium chloride staining.

RESULTS:

Electrogram analysis demonstrated a clear association between electrogram changes and the level of electroporation. Immediately after PFA, electrograms displayed the following: a significant decrease in R/S-wave amplitude; a large elevation of the ST-segment; and a large decrease in their |(dV/dt)|
max
. Marked changes in electrograms were observed beyond the lesion area. Thereafter, a gradual recovery was observed. The evolution of all the electrogram parameters throughout the 60 minutes after PFA was significantly different (
P
<0.05) between the IRE and reversible electroporation areas. Acute lesion staining showed significantly larger depth for PFA lesions compared with radiofrequency ablation.

CONCLUSIONS:
This study shows that unipolar electrograms can differentiate between reversible electroporation and IRE areas during the first 30 minutes post ablation. Differences after the first 30 minutes are less evident. Our findings could result useful for immediate lesion assessment after PFA and warrant further investigation.
Changes in Doppler‐Derived Kidney Venous Flow and Adverse Cardiorenal Outcomes in Patients With Heart Failure
Authors: Husain‐Syed Faeq , Singam Narayana Sarma V. , Viehman Jason K. , Vaughan Lisa , Bauer Pascal , Gall Henning , Tello Khodr , Richter Manuel J. , Yogeswaran Athiththan , Romero‐González Gregorio , Rosner Mitchell H. , Ronco Claudio , Assmus Birgit , Ghofrani Hossein Ardeschir , Seeger Werner , Birk Horst‐Walter , Kashani Kianoush B. 
Published: August 2023

Background
The impact of changes in Doppler‐derived kidney venous flow in heart failure (HF) is not well studied. We aimed to investigate the association of Doppler‐derived kidney venous stasis index (KVSI) and intrakidney venous‐flow (IKVF) patterns with adverse cardiorenal outcomes in patients with HF.

Methods and Results
In this observational cohort study, consecutive inpatients with HF referred to a nephrologist because of a history of diuretic resistance and abnormal kidney function (n=216) underwent spectral kidney assessments after admission (Doppler 1) and 25 to 35 days later (Doppler 2) to identify IKVF patterns (continuous/pulsatile/biphasic/monophasic) and KVSI levels. Cox proportional hazard regression models were used to evaluate the associations between KVSI/IKVF patterns at Doppler 1 as well as changes from Doppler 1 to Doppler 2 and risk of cardiorenal events up to 18 months after admission. Worsening HF or death occurred in 126 patients. Both baseline KVSI (hazard ratio [HR], 1.49 [95% CI, 1.37–1.61] per 0.1‐unit increase) and baseline IKVF pattern (HR, 2.47 [95% CI, 2.01–3.04] per 1 pattern severity increase) were significantly associated with worsening HF/death. Increases in both KVSI and IKVF pattern severity from Doppler 1 to 2 were also associated with an increased risk of worsening HF/death (HR, 3.00 [95% CI, 2.08–4.32] per 0.1‐unit increase change; and HR, 6.73 [95% CI, 3.27–13.86] per 1 pattern increase in severity change, respectively). Similar results were observed for kidney outcomes.

Conclusions
Baseline kidney venous flow predicted adverse cardiorenal events, and inclusion of serial kidney venous flow in cardiorenal risk stratification could facilitate clinical decision‐making for patients with HF.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03039959.
Subclinical Left Ventricular Dysfunction and Ventricular Arrhythmias in Older Adults With Normal Ejection Fraction
Authors: Yoshida Yuriko , Jin Zhezhen , Nakanishi Koki , Matsumoto Kenji , Homma Shunichi , Mannina Carlo , Shames Sofia , Elkind Mitchell S. V. , Rundek Tatjana , Di Tullio Marco R. 
Published: August 2023

Background
Premature ventricular contractions (PVCs) and nonsustained ventricular tachycardia (NSVT) are known to be associated with reduced left ventricular (LV) ejection fraction and adverse outcomes in patients with structural heart disease. The relationship between subclinical LV dysfunction and ventricular arrhythmias in the general population is not established.

Methods and Results

Participants in the SAFARIS (Subclinical Atrial Fibrillation and Risk of Ischemic Stroke) study with normal left ventricular ejection fraction (n=503; mean age 77 years, 63% women) underwent 14‐day electrocardiographic monitoring and 2‐dimensional echocardiography. Frequent PVCs were defined as PVCs >500 per 24 hours and NSVT as ≥4 consecutive ventricular ectopic beats. Reduced LV global longitudinal strain (GLS) was used as an indicator of subclinical LV dysfunction. Seventy‐six participants (15.1%) had PVCs >500/d, 117 (23.3%) had NSVT episodes. LV GLS was significantly reduced in both frequent PVCs and NSVT groups (
P
<0.01). In multivariable analyses, lower LV GLS was associated with frequent PVCs (adjusted odds ratio [aOR], 1.19 [95% CI, 1.09–1.30 per unit reduction];
P
<0.001) and NSVT (aOR, 1.09 [95% CI, 1.01–1.17];
P
=0.036) independently of established risk factors and other echocardiographic parameters. Abnormal LV GLS (>−15.8%) carried a 2‐fold increase in risk of ventricular arrhythmias (aOR, 2.18,
P
=0.029 for PVCs; aOR, 2.09,
P
=0.026 for NSVT).

Conclusions
PVCs and NSVT episodes were frequent in this community‐based elderly cohort with normal left ventricular ejection fraction and were independently associated with lower LV GLS. The association between LV dysfunction and ventricular arrhythmias is present at an early, subclinical stage, an observation that carries possible preventative implications.