bluuebunny/crossref_metadata_2025 huggingface dataset:
Hemodynamic and Management Perspectives in Heart Failure Patients
Authors: Parvathareddy Krishna Mala Konda Reddy , Nagula Praveen
Published: July 2023

Introduction

Prevalence of heart failure (HF) is increasing, and right ventricular (RV) dysfunction is an independent predictor of mortality. Accurate echocardiographic evaluation of RV function is challenging and novel parameters which can aid in prediction RV function are required. Pulmonary artery Pulsatility index (PAPi) is one such parameter.

Patients and Methods

We conducted a prospective study in 33 patients admitted with symptoms of HF and severe LV dysfunction (EF < 35) who underwent right heart catheterization and followed them for 6 months. Primary objective was to determine the association of PAPi with hospitalizations and mortality in short-term follow-up in HF patients. Clinical, demographic, echocardiographic, and catheterization data were recorded. PAPi was calculated as a ratio of pulmonary artery pulse pressure and right atrial pressure.

Results

The mean age of population was 47 years (±12). Males were 20(61%) and females were 13(39%). Median PAPi in the study population was 2.42 (IQR-1.83). The study population were stratified into 3 groups based on 10th, 50th, and 90th percentile PAPi and on comparisons between groups PAPi was significantly associated with hospitalization at 1 and 6 months in univariate ( P = .03 and P = .03 respectively) and in multivariate analysis ( P = .04). PAPi was not found to be associated with mortality at 1 month or 6 months. However, the absolute mortality was low in the study population (n = 4).

Conclusion

PAPi has been found to be a strong and an independent predictor of hospitalization at 1 month and 6 months.

Comments

Advanced HF is seen in 1 out of 5 patients with HF. It is characterized by refractory symptoms, multiple hospitalizations, fluid retention, elevated natriuretic peptides, and decreased cardiac output often requiring inotropes. The survival rate is poor. The presence of right ventricular dysfunction is an independent predictor of mortality in these patients. Hemodynamic assessment is of importance in these patients to guide regarding further management, ie, use of inotropes, left ventricular assist devices, etc. The PAPi is a marker derived from the formula (PASP-PADP/RAP). 1 The outcome worsens as the PAPi decreases. However, the stroke volume, pulmonary artery capacitance (PAC), and right atrial pressure all have an impact on PAPi. Patients with high PAC will have better PAPi compared to those with low PAC with the stroke volume being constant. 2 Different subsets of HF population have varying PAPI thresholds, with isolated RV infarction having the lowest (0.9) and severe HF having the highest (3.2). 2 Future research should examine the impact of exercise, inotropes, and vasodilators.
The Accuracy of Various Lung Ultrasonography Findings in Predicting the Necessity for Surfactant Treatment in Neonates With Respiratory Distress Syndrome
Authors: Ghadiri Asli Seyed Mohammadsadegh , khalilzadeh Sabetmasouleh Ameneh , Akhoundi Neda , Siami Alireza
Published: July 2023

Objective:

The study was conducted to determine the value of various lung ultrasonography (LUS) findings in diagnosing neonatal respiratory distress syndrome (RDS) and to assess the ability of ultrasonography to predict the need for surfactant treatment.

Materials and Methods:

This cohort study was conducted on 164 neonates with RDS with a gestational age of over 28 weeks. Transthoracic sonography was performed in all patients in the infant isolet immediately after admission and stabilization of the infant and during the first 6 hours before surfactant treatment. Immediately after the sonogram, the neonates underwent an anterior–posterior view chest radiograph, before and after surfactant treatment.

Results:

In comparison with clinical manifestations and radiographic findings as the references, the sensitivity and specificity of each of the LUS-related parameters for detecting RDS were as follows: Faded A-lines (95.4% and 76.7%), abnormal B-lines (91.7% and 71.6%), the presence of consolidation (90.9% and 88.3%), the presence of pleural effusion (95% and 86.7%), and alveolar–interstitial syndrome (AIS) (98% and 96%).

Conclusion:

LUS findings were valuable in assessing and grading the severity of neonatal RDS alongside clinical evaluation. LUS may assist in selecting infants for surfactant therapy and monitoring treatment response.
Genetically encoded phosphatidylserine biosensor for in vitro, ex vivo and in vivo labelling
Authors: Dirvelyte Eimina , Bujanauskiene Daina , Jankaityte Evelina , Daugelaviciene Neringa , Kisieliute Ugne , Nagula Igor , Budvytyte Rima , Neniskyte Urte
Published: July 2023

Background

The dynamics of phosphatidylserine in the plasma membrane is a tightly regulated feature of eukaryotic cells. Phosphatidylserine (PS) is found preferentially in the inner leaflet of the plasma membrane. Disruption of this asymmetry leads to the exposure of phosphatidylserine on the cell surface and is associated with cell death, synaptic pruning, blood clotting and other cellular processes. Due to the role of phosphatidylserine in widespread cellular functions, an efficient phosphatidylserine probe is needed to study them. Currently, a few different phosphatidylserine labelling tools are available; however, these labels have unfavourable signal-to-noise ratios and are difficult to use in tissues due to limited permeability. Their application in living tissue requires injection procedures that damage the tissue and release damage-associated molecular patterns, which in turn stimulates phosphatidylserine exposure.

Methods

For this reason, we developed a novel genetically encoded phosphatidylserine probe based on the C2 domain of the lactadherin (MFG-E8) protein, suitable for labelling exposed phosphatidylserine in various research models. We tested the C2 probe specificity to phosphatidylserine on hybrid bilayer lipid membranes by observing surface plasmon resonance angle shift. Then, we analysed purified fused C2 proteins on different cell culture lines or engineered AAVs encoding C2 probes on tissue cultures after apoptosis induction. For in vivo experiments, neurotropic AAVs were intravenously injected into perinatal mice, and after 2 weeks, brain slices were collected to observe C2-SNAP expression.

Results

The biophysical analysis revealed the high specificity of the C2 probe for phosphatidylserine. The fused recombinant C2 proteins were suitable for labelling phosphatidylserine on the surface of apoptotic cells in various cell lines. We engineered AAVs and validated them in organotypic brain tissue cultures for non-invasive delivery of the genetically encoded C2 probe and showed that these probes were expressed in the brain in vivo after intravenous AAV delivery to mice.

Conclusions

We have demonstrated that the developed genetically encoded PS biosensor can be utilised in a variety of assays as a two-component system of C2 and C2m2 fusion proteins. This system allows for precise quantification and PS visualisation at directly specified threshold levels, enabling the evaluation of PS exposure in both physiological and cell death processes.
Lineage-specific amplification and epigenetic regulation of LTR-retrotransposons contribute to the structure, evolution, and function of Fabaceae species
Authors: Yang Long-Long , Zhang Xin-Yu , Wang Li-Ying , Li Yan-Ge , Li Xiao-Ting , Yang Yi , Su Qing , Chen Ning , Zhang Yu-Lan , Li Ning , Deng Chuan-Liang , Li Shu-Fen , Gao Wu-Jun
Published: July 2023

Background

Long terminal repeat (LTR)-retrotransposons (LTR-RTs) are ubiquitous and make up the majority of nearly all sequenced plant genomes, whereas their pivotal roles in genome evolution, gene expression regulation as well as their epigenetic regulation are still not well understood, especially in a large number of closely related species.

Results

Here, we analyzed the abundance and dynamic evolution of LTR-RTs in 54 species from an economically and agronomically important family, Fabaceae, and also selected two representative species for further analysis in expression of associated genes, transcriptional activity and DNA methylation patterns of LTR-RTs. Annotation results revealed highly varied proportions of LTR-RTs in these genomes (5.1%~68.4%) and their correlation with genome size was highly positive, and they were significantly contributed to the variance in genome size through species-specific unique amplifications. Almost all of the intact LTR-RTs were inserted into the genomes 4 Mya (million years ago), and more than 50% of them were inserted in the last 0.5 million years, suggesting that recent amplifications of LTR-RTs were an important force driving genome evolution. In addition, expression levels of genes with intronic, promoter, and downstream LTR-RT insertions of Glycine max and Vigna radiata, two agronomically important crops in Fabaceae, showed that the LTR-RTs located in promoter or downstream regions suppressed associated gene expression. However, the LTR-RTs within introns promoted gene expression or had no contribution to gene expression. Additionally, shorter and younger LTR-RTs maintained higher mobility and transpositional potential. Compared with the transcriptionally silent LTR-RTs, the active elements showed significantly lower DNA methylation levels in all three contexts. The distributions of transcriptionally active and silent LTR-RT methylation varied across different lineages due to the position of LTR-RTs located or potentially epigenetic regulation.

Conclusion

Lineage-specific amplification patterns were observed and higher methylation level may repress the activity of LTR-RTs, further influence evolution in Fabaceae species. This study offers valuable clues into the evolution, function, transcriptional activity and epigenetic regulation of LTR-RTs in Fabaceae genomes.
Mobile care - a possible future for emergency care in Sweden
Authors: Teske Christofer , Mourad Ghassan , Milovanovic Micha
Published: July 2023

Introduction

Provision of mobile care at the home of patients appears to become necessary as the population becomes increasingly older. But there are challenges in moving emergency care from hospitals to the home of patients. The aim of the study was therefore to describe the experiences of the mobile care in Sweden.

Method

Semi structured interviews were conducted with 12 persons with experience of mobile care in Sweden, such as nurses, physicians, civil servants and politicians. Qualitative latent content analysis was used as an analysis method.

Result

The results show that cooperation is of utmost importance to achieve functioning mobile care. Cooperation both on an inter-organizational level and on a close team-work is required for all of the involved parties in mobile care to take on a joint responsibility for the patient. As mobile care is primarily provided to elderly multimorbid patients, a comprehensive view on patient care is required in which the patient and their relatives experience security.

Conclusion

Mobile care is seen as a moving care that comes to the seeking person and not the other way around. The resources are distributed where they make the most use, that is, closest to the individual. Mobile care is seen as a complement to the traditional hospital care. This means a different way of working that requires close collaboration between different categories of personnel and organizations, where there should not be any discussions about boundaries, rather, the discussion should include patient’s needs and situation instead.
Epidemiology and outcomes of choledocholithiasis and cholangitis in the United States: trends and urban-rural variations
Authors: Li Suqing , Guizzetti Leonardo , Ma Christopher , Shaheen Abdel Aziz , Dixon Elijah , Ball Chad , Wani Sachin , Forbes Nauzer
Published: July 2023

Background

Gallstone disease poses a significant health burden in the United States. Choledocholithiasis and cholangitis are common complications of gallstone disease for which data on current epidemiological trends are lacking. We aimed to evaluate temporal changes in hospitalization, management, and outcomes for patients with choledocholithiasis and cholangitis.

Methods

The National Inpatient Sample was used to identify discharges for choledocholithiasis and cholangitis between 2005 and 2014. Temporal trends were evaluated via annual percent changes (APCs). Joinpoint regression was used to assess inflection points. Multivariable regression models were used to evaluate associations of interest.

Results

From 189,362 unweighted discharges for choledocholithiasis and/or cholangitis, there was an increase in discharges for choledocholithiasis (APC 2.3%, 95% confidence intervals, CI, 1.9–2.7%) and cholangitis (APC 1.5%, 95% CI 0.7–2.2%). Procedural interventions were more likely at urban hospitals for choledocholithiasis (adjusted odds ratio, aOR, 2.94, 95% CI 2.72 to 3.17) and cholangitis (aOR 2.97, 95% CI 2.50 to 3.54). In-hospital mortality significantly decreased annually for choledocholithiasis (aOR 0.90, 95% CI 0.88 to 0.93) and cholangitis (aOR 0.93, 95% CI 0.89 to 0.97). In-hospital mortality between rural and urban centers was comparable for choledocholithiasis (aOR 1.16, 95% CI 0.89 to 1.52) and cholangitis (aOR 1.12, 95% CI 0.72 to 1.72).

Conclusions

Hospitalizations for choledocholithiasis and cholangitis have increased between 2005 and 2014, reflecting a growing burden of gallstone disease. Hospital mortality between urban and rural centers is similar, however urban centers have a higher rate of procedural interventions suggesting limitations to accessing procedural interventions at rural centers.
Do antenatal preparation and obstetric complications and procedures interact to affect birth experience and postnatal mental health?
Authors: Cross Hannah , Krahé Charlotte , Spiby Helen , Slade Pauline
Published: July 2023

Background

Antenatal preparation is commonly offered to women in pregnancy in the United Kingdom, but the content is highly variable, with some programmes orientated towards ‘normal birth’, whilst others may incorporate information about complications and procedures (broader focus). However, the impact of this variability on birth experience has not been explored. We examined the relationship between the content of antenatal preparation received and birth experience, taking into account obstetric complications and procedures. As birth experience can have a profound impact on a mother’s postnatal well-being, we also investigated associations with mothers’ postnatal mood and anxiety.

Methods

N = 253 first-time mothers completed a cross-sectional survey measuring demographic and clinical factors, antenatal preparation content (categorised as normality-focused or broader-focused), obstetric complications and procedures experienced, birth experience (measured using three separate indices; the Childbirth Experience Questionnaire, emotional experiences, and presence/absence of birth trauma), postnatal depression and anxiety, and qualitative information on how the COVID-19 pandemic had affected birth experience.

Results

Regarding birth experience, receiving more broader-focused preparation was associated with a more positive birth experience irrespective of complications/procedures experienced, while receiving only normality-focused preparation was beneficial in the context of fewer complications/procedures. Regarding birth trauma, receiving more broader-focused preparation was associated with lower likelihood of reporting birth as traumatic only in the context of more complications/procedures. Degree of normality-focused preparation was unrelated to experience of birth trauma. Lastly, while more complications/procedures were associated with greater anxiety and low mood, only greater normality-focused preparation was linked with better postnatal mental health.

Conclusions

Antenatal preparation including both normality- and broader-focused information is positively related to women’s birth experience. While normality-focused preparation seems most beneficial if fewer complications/procedures are experienced, broader-focused preparation may be most beneficial in the context of a greater number of complications/procedures. As complications/procedures are often unpredictable, offering broader-focused preparation routinely is likely to benefit women’s birth experience. This antenatal preparation should be freely available and easily accessible.
Keratoconus International Consortium (KIC)- advancing keratoconus research
Authors: Sahebjada Srujana , Chan Elsie , Sutton Gerard , Pang Chi Pui Calvin ,   Srujana Sahebjada for KIC Members, Hodge Christopher , Chong Elaine W. , Zemani-Fodil Faouzia , Wiffen Steve , Snibson Grant , Morlet Nigel , Samarawickrama Chameen , Males John , Mills Richard , Beckingsale Peter , Burdon Kathryn , Jhanji Vishal , Krishna Pravin , Chan Colin , Tenen Abi , Roufas Athena , Huynh Tess , Vajpayee Rasik , Gupta Aanchal , Silva Marcelo Reyes , Zarei Mehran , Kumaran Senthil , Huang Guofu , Seitz Berthold , Ren Shengwei , McGhee Charles , Barker Nigel , Kerdraon Yves , Natarajan Sundaram , Meteoukki Wafaa , Ang Andrea , Daniell Mark , Baird Paul N.
Published: July 2023

Clinical relevance

The Keratoconus International Consortium (KIC) will allow better understanding of keratoconus.

Background

Keratoconus is a disorder characterised by corneal elevation and thinning, leading to reduced vision. The current gaps in understanding of this disease will be discussed and the need for a multi-pronged and multi-centre engagement to enhance our understanding of keratoconus will be highlighted.

Design

KIC has been established to address the gaps in our understanding of keratoconus with the aim of collecting baseline as well as longitudinal data on several fields.

Participants

Keratoconus and control (no corneal condition) subjects from different sites globally will be recruited in the study.

Methods

KIC collects data using an online, secure database, which enables standardised data collection at member sites. Data fields collected include medical history, clinical features, quality of life and economic burden questionnaires and possible genetic sample collection from patients of different ethnicities across different geographical locations.

Results

There are currently 40 Australian and international clinics or hospital departments who have joined the KIC. Baseline data has so far been collected on 1130 keratoconus patients and indicates a median age of 29.70 years with 61% being male. A total of 15.3% report a positive family history of keratoconus and 57.7% self-report a history of frequent eye rubbing.

Conclusion

The strength of this consortium is its international, collaborative design and use of a common data collection tool. Inclusion and analyses of cross-sectional and longitudinal data will help answer many questions that remain in keratoconus, including factors affecting progression and treatment outcomes.
Primary Sjögren’s syndrome misdiagnosed as Mikulicz’s disease: a case report
Authors: Ren Tingting , Liu Rui , Li Jing , Ma Jianmin
Published: July 2023

Background

Sjögren’s Syndrome (SS) is an inflammatory autoimmune disease, and Mikulicz’s disease (MD) is a lymphoproliferative disorder. Both MD and SS are more common in middle-aged female, and the dry eyes could be presented in both of them with different degree. The MD patients are characterized by symmetrical swelling of the lacrimal glands which also can occur in the early stage of SS. And the imaging findings between early stage of SS and MD are lack of specificity. Therefore, SS and MD have similarities in the clinical manifestations, imaging and pathological findings and are confused in diagnosis.

Case presentation

A 51-year-old female patient presented with bilateral swelling of the upper eyelids for 2 years. She also reported having dry mouth and dry eyes which could be tolerated. The Schirmer’s test result is positive and the laboratory tests indicate serum total IgG increased. In the bilateral lacrimal gland area could palpate soft masses. The orbital magnetic resonance imaging (MRI) examination showed bilateral lacrimal gland prolapse. While the histopathological result was considered as MD. The immunohistochemical (IHC) staining results were positive for IgG and negative for IgG4. To clarify the diagnosis, SS-related laboratory tests were performed: anti-SSA antibody (+++), anti-SSB antibody (+++), anti-Ro-52 antibody (+++). With a comprehensive consideration, the final diagnosis was SS.

Conclusion

When the clinical manifestations are atypical, it is necessary to pay attention to the differential diagnosis of SS and MD.
What causes concordance of hypertension between spouses in India? Identifying a critical knowledge gap from a nationally representative cross-sectional sample of 63,020 couples aged 15 + years
Authors: Nayak Gayatri , Ghosal Shishirendu , Ghosal Jyoti , Dutta Ambarish
Published: July 2023

Background

Hypertension, a critical risk factor for cardiovascular diseases, is found to cluster between spouses due to within-couple aggregation of antecedent environmental risk factors, either through assortative mating or cohabitation. However, majority of the evidence of spousal concordance of hypertension is from Caucasoid couples from western societies, whereas marriage, partner selection, and post-marital roles of husband and wives are very different in Indian society. Therefore, we aimed to comprehensively examine the phenomenon of spousal concordance of hypertension in Indian couples.

Method

Couples from Longitudinal Ageing Study in India Wave 1 (n = 10,994) and National Family Health Survey Round 5 (n = 52,026) represented 15 years + Indian spouses. Hypertension was defined when systolic and/or diastolic blood pressure was > 139 and > 89 mmHg respectively, and/or if the individual was previously diagnosed or on anti-hypertensive medication. Odds Ratios (OR) estimated the within-couple concordance of hypertension while adjusting for five environmental risk factors of hypertension: individual-level body mass index, education and caste, and household-level wealth and place of residence.

Result

OR marginally attenuated from 1.84 (95% Confidence Interval: 1.77, 1.92) to 1.75 (1.68, 1.83) after adjustment, signifying negligible explanation by environmental risk factors, and plausibility of “novel” risk factors. Concordance continued to weaken with age (OR: 2.25 (2.02, 2.52) in < 30 versus 1.36 (1.20, 1.53) in ≥ 60 years).

Conclusion

Our study underscores two critical knowledge gaps: first, the identity of “novel” risk factors of hypertension and second, the mechanism behind weakening of concordance with age. Future research should explore these novel risk factors rigorously and try to modify them. Also, primary healthcare policy of the country should focus on couples in addition to individuals for hypertension and cardiovascular disease screening and management.
Video-assisted thoracoscopic surgery simulation and training: a comprehensive literature review
Authors: Grossi Sarah , Cattoni Maria , Rotolo Nicola , Imperatori Andrea
Published: July 2023

Background

Video-assisted thoracic surgery (VATS) has become the standard for lung cancer diagnosis and treatment. However, this surgical technique requires specific and dedicated training. In the past 20 years, several simulator systems have been developed to promote VATS training. Advances in virtual reality may facilitate its integration into the VATS training curriculum. The present review aims to first provide a comprehensive overview of the simulators for thoracoscopic surgery, focused especially on simulators for lung lobectomy; second, it explores the role and highlights the possible efficacy of these simulators in the surgical trainee curriculum.

Methods

A literature search was conducted in the PubMed, EMBASE, Science Direct, Scopus and Web of Science databases using the following keywords combined with Boolean operators “AND” and “OR”: virtual reality, VR, augmented reality, virtual simulation, mixed reality, extended reality, thoracic surgery, thoracoscopy, VATS, video-assisted thoracoscopic surgery, simulation, simulator, simulators, training, and education. Reference lists of the identified articles were hand-searched for additional relevant articles to be included in this review.

Results

Different types of simulators have been used for VATS training: synthetic lung models (dry simulators); live animals or animal tissues (wet simulators); and simulators based on virtual or augmented reality. Their role in surgical training has been generally defined as useful. However, not enough data are available to ascertain which type is the most appropriate.

Conclusions

Simulator application in the field of medical education could revolutionize the regular surgical training curriculum. Further studies are required to better define their impact on surgeons’ training programs and, finally, on patients’ quality of care.
Validation of the attitudes towards people living with HIV/AIDS scale in nursing students
Authors: Gázquez-López María , García-García Inmaculada , González-García Alberto , Martín-Salvador Adelina , Pérez-Morente María Ángeles , Martínez-García Encarnación , Álvarez-Serrano María Adelaida
Published: July 2023

Background

One of the environments where people living with HIV/AIDS should feel safer is in the health care setting; however, scientific evidence has identified discriminatory behaviour on the part of health care professionals towards these people. The reduction or abolition of discriminatory practices requires, first of all, to know the attitudes of nursing students towards AIDS with tools appropriate to the socio-cultural context of the disease. The objectives of this study are to update the AIDS Attitudes Scale for Nursing Students (EASE) by adapting it to the sociocultural landscape and to analyse the reliability and structural validity of the new scale.

Methods

The results of the questionnaires answered by 213 undergraduate nursing students from the Faculty of Health Sciences of Ceuta (University of Granada) were analysed. Reliability (test-retest, n = 33) and validity (n = 180) tests were carried out.

Results

An exploratory and confirmatory factor analysis indicated that a four-factor model was the most parsimonious solution. Items were examined for their underlying relationships and labelled: professional practice, social integration, partner and family, and benevolent stigma. The new scale yielded a McDonald’s Omega coefficient (ω) of 0.893. Convergent validity was established for average variance extracted per factor greater than 0.5 and divergent validity when the variance retained by each factor is greater than the variance shared between them (average variance extracted per factor > ϕ2).

Conclusions

The new scale is a psychometrically sound instrument for assessing attitudes towards people living with HIV/AIDS in nursing students.
Risk factors for human papillomavirus infection, cervical intraepithelial neoplasia and cervical cancer: an umbrella review and follow-up Mendelian randomisation studies
Authors: Bowden Sarah J. , Doulgeraki Triada , Bouras Emmanouil , Markozannes Georgios , Athanasiou Antonios , Grout-Smith Harriet , Kechagias Konstantinos S. , Ellis Laura Burney , Zuber Verena , Chadeau-Hyam Marc , Flanagan James M. , Tsilidis Konstantinos K. , Kalliala Ilkka , Kyrgiou Maria
Published: July 2023

Background

Persistent infection by oncogenic human papillomavirus (HPV) is necessary although not sufficient for development of cervical cancer. Behavioural, environmental, or comorbid exposures may promote or protect against malignant transformation. Randomised evidence is limited and the validity of observational studies describing these associations remains unclear.

Methods

In this umbrella review, we searched electronic databases to identify meta-analyses of observational studies that evaluated risk or protective factors and the incidence of HPV infection, cervical intra-epithelial neoplasia (CIN), cervical cancer incidence and mortality. Following re-analysis, evidence was classified and graded based on a pre-defined set of statistical criteria. Quality was assessed with AMSTAR-2. For all associations graded as weak evidence or above, with available genetic instruments, we also performed Mendelian randomisation to examine the potential causal effect of modifiable exposures with risk of cervical cancer. The protocol for this study was registered on PROSPERO (CRD42020189995).

Results

We included 171 meta-analyses of different exposure contrasts from 50 studies. Systemic immunosuppression including HIV infection (RR = 2.20 (95% CI = 1.89–2.54)) and immunosuppressive medications for inflammatory bowel disease (RR = 1.33 (95% CI = 1.27–1.39)), as well as an altered vaginal microbiome (RR = 1.59 (95% CI = 1.40–1.81)), were supported by strong and highly suggestive evidence for an association with HPV persistence, CIN or cervical cancer. Smoking, number of sexual partners and young age at first pregnancy were supported by highly suggestive evidence and confirmed by Mendelian randomisation.

Conclusions

Our main analysis supported the association of systemic (HIV infection, immunosuppressive medications) and local immunosuppression (altered vaginal microbiota) with increased risk for worse HPV and cervical disease outcomes. Mendelian randomisation confirmed the link for genetically predicted lifetime smoking index, and young age at first pregnancy with cervical cancer, highlighting also that observational evidence can hide different inherent biases. This evidence strengthens the need for more frequent HPV screening in people with immunosuppression, further investigation of the vaginal microbiome and access to sexual health services.
Metabolic systems approaches update molecular insights of clinical phenotypes and cardiovascular risk in patients with homozygous familial hypercholesterolemia
Authors: Du Zhiyong , Li Fan , Jiang Long , Li Linyi , Du Yunhui , Yu Huahui , Luo Yan , Wang Yu , Sun Haili , Hu Chaowei , Li Jianping , Yang Ya , Jiao Xiaolu , Wang Luya , Qin Yanwen
Published: July 2023

Background

Homozygous familial hypercholesterolemia (HoFH) is an orphan metabolic disease characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C), xanthomas, aortic stenosis, and premature atherosclerotic cardiovascular disease (ASCVD). In addition to LDL-C, studies in experimental models and small clinical populations have suggested that other types of metabolic molecules might also be risk factors responsible for cardiovascular complications in HoFH, but definitive evidence from large-scale human studies is still lacking. Herein, we aimed to comprehensively characterize the metabolic features and risk factors of human HoFH by using metabolic systems strategies.

Methods

Two independent multi-center cohorts with a total of 868 individuals were included in the cross-sectional study. First, comprehensive serum metabolome/lipidome-wide analyses were employed to identify the metabolomic patterns for differentiating HoFH patients (n = 184) from heterozygous FH (HeFH, n = 376) and non-FH (n = 100) subjects in the discovery cohort. Then, the metabolomic patterns were verified in the validation cohort with 48 HoFH patients, 110 HeFH patients, and 50 non-FH individuals. Subsequently, correlation/regression analyses were performed to investigate the associations of clinical/metabolic alterations with typical phenotypes of HoFH. In the prospective study, a total of 84 HoFH patients with available follow-up were enrolled from the discovery cohort. Targeted metabolomics, deep proteomics, and random forest approaches were performed to investigate the ASCVD-associated biomarkers in HoFH patients.

Results

Beyond LDL-C, various bioactive metabolites in multiple pathways were discovered and validated for differentiating HoFH from HoFH and non-FH. Our results demonstrated that the inflammation and oxidative stress-related metabolites in the pathways of arachidonic acid and lipoprotein(a) metabolism were independently associated with the prevalence of corneal arcus, xanthomas, and supravalvular/valvular aortic stenosis in HoFH patients. Our results also identified a small marker panel consisting of high-density lipoprotein cholesterol, lipoprotein(a), apolipoprotein A1, and eight proinflammatory and proatherogenic metabolites in the pathways of arachidonic acid, phospholipid, carnitine, and sphingolipid metabolism that exhibited significant performances on predicting first ASCVD events in HoFH patients.

Conclusions

Our findings demonstrate that human HoFH is associated with a variety of metabolic abnormalities and is more complex than previously known. Furthermore, this study provides additional metabolic alterations that hold promise as residual risk factors in HoFH population.
Internally versus externally trained residents and fellows hired as attendings at a large integrated healthcare system: a 20-year retrospective study
Authors: Wertheimer Stephen M. , Harris Jerad A. , Collins J. Craig , Spiegel Nancy H. , Chien Gary W.
Published: July 2023

Background

There remains a question of whether graduates trained internally are different than those trained elsewhere. We examine the difference between physicians trained within our Graduate Medical Education (GME) programs versus physicians trained elsewhere. Our large integrated healthcare system is unique in addressing this objective due to its large physician labor hiring needs across different specialties of GME graduates.

Methods

A retrospective review was performed from Jan 2000 to August 2020 of Kaiser Permanente Southern California (KPSC) physicians hired: KPSC GME trained versus non-KPSC GME trained. We examined five variables: retention, leadership (current or historical), physician relations cases, member appraisal of physician and provider services survey (MAPPS) scores, and rate of board certification. Chi-square test of proportions was used for comparison, p < 0.05 was significant.

Results

From Jan 2000 to August 2020, 2940 residents and fellows graduated from KPSC GME programs, of which 1127 (38%) were hired on at KPSC as full time attendings. Across all five metrics (Retention 82% vs 76% (p =  < 0.01), Leadership [current 13% vs 10% (p =  < 0.01)or historical 17% vs 14% (p = 0.01)], Physician Relations 23% vs 26% (p = 0.04), MAPPS 75% vs 69% (p =  < 0.01), and Board Certification 81% vs 74% (p =  < 0.01)), KPSC outperformed non-KPSC GME-trained physicians to a statistically significant degree.

Conclusions

We have shown that an internally sponsored GME program can represent an opportunity for recruitment of physicians that may have higher retention rates, higher probability of being physician leaders, decreased likelihood of physician relations issues, improved patient satisfaction, and increased rates of board certification.
Radiomics using computed tomography to predict CD73 expression and prognosis of colorectal cancer liver metastases
Authors: Saber Ralph , Henault David , Messaoudi Nouredin , Rebolledo Rolando , Montagnon Emmanuel , Soucy Geneviève , Stagg John , Tang An , Turcotte Simon , Kadoury Samuel
Published: July 2023

Background

Finding a noninvasive radiomic surrogate of tumor immune features could help identify patients more likely to respond to novel immune checkpoint inhibitors. Particularly, CD73 is an ectonucleotidase that catalyzes the breakdown of extracellular AMP into immunosuppressive adenosine, which can be blocked by therapeutic antibodies. High CD73 expression in colorectal cancer liver metastasis (CRLM) resected with curative intent is associated with early recurrence and shorter patient survival. The aim of this study was hence to evaluate whether machine learning analysis of preoperative liver CT-scan could estimate high vs low CD73 expression in CRLM and whether such radiomic score would have a prognostic significance.

Methods

We trained an Attentive Interpretable Tabular Learning (TabNet) model to predict, from preoperative CT images, stratified expression levels of CD73 (CD73Highvs. CD73Low) assessed by immunofluorescence (IF) on tissue microarrays. Radiomic features were extracted from 160 segmented CRLM of 122 patients with matched IF data, preprocessed and used to train the predictive model. We applied a five-fold cross-validation and validated the performance on a hold-out test set.

Results

TabNet provided areas under the receiver operating characteristic curve of 0.95 (95% CI 0.87 to 1.0) and 0.79 (0.65 to 0.92) on the training and hold-out test sets respectively, and outperformed other machine learning models. The TabNet-derived score, termed rad-CD73, was positively correlated with CD73 histological expression in matched CRLM (Spearman’sρ = 0.6004;P < 0.0001). The median time to recurrence (TTR) and disease-specific survival (DSS) after CRLM resection in rad-CD73Highvs rad-CD73Lowpatients was 13.0 vs 23.6 months (P = 0.0098) and 53.4 vs 126.0 months (P = 0.0222), respectively. The prognostic value of rad-CD73 was independent of the standard clinical risk score, for both TTR (HR = 2.11, 95% CI 1.30 to 3.45,P < 0.005) and DSS (HR = 1.88, 95% CI 1.11 to 3.18,P = 0.020).

Conclusions

Our findings reveal promising results for non-invasive CT-scan-based prediction of CD73 expression in CRLM and warrant further validation as to whether rad-CD73 could assist oncologists as a biomarker of prognosis and response to immunotherapies targeting the adenosine pathway.
Immunostimulatory gene therapy targeting CD40, 4-1BB and IL-2R activates DCs and stimulates antigen-specific T-cell and NK-cell responses in melanoma models
Authors: Wenthe Jessica , Eriksson Emma , Hellström Ann-Charlotte , Moreno Rafael , Ullenhag Gustav , Alemany Ramon , Lövgren Tanja , Loskog Angelica
Published: July 2023

Background

The activation of dendritic cells (DCs) is pivotal for generating antigen-specific T-cell responses to eradicate tumor cells. Hence, immunotherapies targeting this interplay are especially intriguing. Moreover, it is of interest to modulate the tumor microenvironment (TME), as this harsh milieu often impairs adaptive immune responses. Oncolytic viral therapy presents an opportunity to overcome the immunosuppression in tumors by destroying tumor cells and thereby releasing antigens and immunostimulatory factors. These effects can be further amplified by the introduction of transgenes expressed by the virus.

Methods

Lokon oncolytic adenoviruses (LOAd) belong to a platform of chimeric serotype Ad5/35 viruses that have their replication restricted to tumor cells, but the expression of transgenes is permitted in all infected cells. LOAd732 is a novel oncolytic adenovirus that expresses three essential immunostimulatory transgenes: trimerized membrane-bound CD40L, 4-1BBL and IL-2. Transgene expression was determined with flow cytometry and ELISA and the oncolytic function was evaluated with viability assays and xenograft models. The activation profiles of DCs were investigated in co-cultures with tumor cells or in an autologous antigen-specific T cell model by flow cytometry and multiplex proteomic analysis. Statistical differences were analyzed with Kruskal–Wallis test followed by Dunn’s multiple comparison test.

Results

All three transgenes were expressed in infected melanoma cells and DCs and transgene expression did not impair the oncolytic activity in tumor cells. DCs were matured post LOAd732 infection and expressed a multitude of co-stimulatory molecules and pro-inflammatory cytokines crucial for T-cell responses. Furthermore, these DCs were capable of expanding and stimulating antigen-specific T cells in addition to natural killer (NK) cells. Strikingly, the addition of immunosuppressive cytokines TGF-β1 and IL-10 did not affect the ability of LOAd732-matured DCs to expand antigen-specific T cells and these cells retained an enhanced activation profile.

Conclusions

LOAd732 is a novel immunostimulatory gene therapy based on an oncolytic adenovirus that expresses three transgenes, which are essential for mediating an anti-tumor immune response by activating DCs and stimulating T and NK cells even under imunosuppressive conditions commonly present in the TME. These qualities make LOAd732 an appealing new immunotherapy approach.
Machine learning in Huntington’s disease: exploring the Enroll-HD dataset for prognosis and driving capability prediction
Authors: Ouwerkerk Jasper , Feleus Stephanie , van der Zwaan Kasper F. , Li Yunlei , Roos Marco , van Roon-Mom Willeke M. C. , de Bot Susanne T. , Wolstencroft Katherine J. , Mina Eleni
Published: July 2023

Background

In biomedicine, machine learning (ML) has proven beneficial for the prognosis and diagnosis of different diseases, including cancer and neurodegenerative disorders. For rare diseases, however, the requirement for large datasets often prevents this approach. Huntington’s disease (HD) is a rare neurodegenerative disorder caused by a CAG repeat expansion in the coding region of the huntingtin gene. The world’s largest observational study for HD, Enroll-HD, describes over 21,000 participants. As such, Enroll-HD is amenable to ML methods. In this study, we pre-processed and imputed Enroll-HD with ML methods to maximise the inclusion of participants and variables. With this dataset we developed models to improve the prediction of the age at onset (AAO) and compared it to the well-established Langbehn formula. In addition, we used recurrent neural networks (RNNs) to demonstrate the utility of ML methods for longitudinal datasets, assessing driving capabilities by learning from previous participant assessments.

Results

Simple pre-processing imputed around 42% of missing values in Enroll-HD. Also, 167 variables were retained as a result of imputing with ML. We found that multiple ML models were able to outperform the Langbehn formula. The best ML model (light gradient boosting machine) improved the prognosis of AAO compared to the Langbehn formula by 9.2%, based on root mean squared error in the test set. In addition, our ML model provides more accurate prognosis for a wider CAG repeat range compared to the Langbehn formula. Driving capability was predicted with an accuracy of 85.2%. The resulting pre-processing workflow and code to train the ML models are available to be used for related HD predictions at: https://github.com/JasperO98/hdml/tree/main.

Conclusions

Our pre-processing workflow made it possible to resolve the missing values and include most participants and variables in Enroll-HD. We show the added value of a ML approach, which improved AAO predictions and allowed for the development of an advisory model that can assist clinicians and participants in estimating future driving capability.
Ten years of treatment with ruxolitinib for myelofibrosis: a review of safety
Authors: Verstovsek Srdan , Mesa Ruben A. , Livingston Robert A. , Hu Wilson , Mascarenhas John
Published: July 2023

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, anemia, extramedullary hematopoiesis, and splenomegaly. Patients with MF are at risk for reduced survival versus the general population and often experience burdensome signs and symptoms that reduce quality of life. The oral Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib was initially approved by the US Food and Drug Administration in 2011 for the treatment of patients with intermediate or high-risk MF, including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF, based on efficacy and safety findings from the randomized, controlled, phase 3 COMFORT trials. Over a decade later, ruxolitinib continues to be the standard of care in higher-risk MF, and dose optimization and management remain crucial for safely maximizing clinical benefits of ruxolitinib. This review summarizes the safety profile of ruxolitinib in patients with MF in the COMFORT trials leading up to approval and in the subsequent JUMP, ROBUST, EXPAND, and REALISE trials; in pooled analyses; and in postmarketing analyses in the 10 years following approval. There is a focus on the occurrence of common hematologic and nonhematologic adverse events, with guidance provided on the management of patients with anemia or thrombocytopenia, including dosing strategies based on findings from the REALISE and EXPAND trials. Finally, to ensure a greater understanding of the safety profile of ruxolitinib, practical considerations are discussed.
Opportunistic channel estimation with LTE signals of limited bandwidth for positioning applications
Authors: Pin A. , Rinaldo R. , Tonello A. , Marshall C. , Driusso M. , Biason A. , Dalla Torre A.
Published: July 2023

The positioning problem is interesting in a variety of applications, especially in indoor environments or in urban canyons, where the position information obtainable with traditional Global Navigation Satellite Systems is limited. In this paper, we deal with the problem of estimating, for the purposes of positioning, the time of arrival (TOA) and the angle of arrival (AOA) by processing LTE 3GPP signals, with particular attention to the uplink signals. The main contribution of this paper is the definition of new opportunistic methods to estimate the TOA and the AOA using the upstream demodulation reference signal (DM-RS) instead of the Sounding Reference Signal. We will show that the use of DM-RS and of estimation algorithms such as the Space-Alternating Generalized Expectation-Maximization and the Iterative Adaptive Approach for Amplitude and Phase estimation (IAA-APES) allows an efficient estimate of the parameters, in spite of the small, occupied bandwidth.
Generalized UH-stability of a nonlinear fractional coupling $(\mathcalligra{p}_{1},\mathcalligra{p}_{2})$-Laplacian system concerned with nonsingular Atangana–Baleanu fractional calculus
Authors: Zhao Kaihong
Published: July 2023

The classical $\mathcalligra{p}$
p
-Laplace equation is one of the special and significant second-order ODEs. The fractional-order $\mathcalligra{p}$
p
-Laplace ODE is an important generalization. In this paper, we mainly treat with a nonlinear coupling $(\mathcalligra{p}_{1},\mathcalligra{p}_{2})$
(

p
1

,

p
2

)
-Laplacian systems involving the nonsingular Atangana–Baleanu (AB) fractional derivative. In accordance with the value range of parameters $\mathcalligra{p}_{1}$

p
1

and $\mathcalligra{p}_{2}$

p
2

, we obtain sufficient criteria for the existence and uniqueness of solution in four cases. By using some inequality techniques we further establish the generalized UH-stability for this system. Finally, we test the validity and practicality of the main results by an example.
On the unconstrained optimization reformulations for a class of stochastic vector variational inequality problems
Authors: Dong Dan-dan , Tang Guo-ji , Qiu Hui-ming
Published: July 2023

In this paper, a class of stochastic vector variational inequality (SVVI) problems are considered. By employing the idea of a D-gap function, the SVVI problem is reformulated as a deterministic model, which is an unconstrained expected residual minimization (UERM) problem, while it is reformulated as a constrained expected residual minimization problem in the work of Zhao et al. Then, the properties of the objective function are investigated and a sample average approximation approach is proposed for solving the UERM problem. Convergence of the proposed approach for global optimal solutions and stationary points is analyzed. Moreover, we consider another deterministic formulation, i.e., the expected value (EV) formulation for an SVVI problem, and the global error bound of a D-gap function based on the EV formulation is given.