bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultra-early myocardial calcification secondary to fulminant myocarditis with 4 years of follow-up: a case report
Authors: You Binquan , Zeng Congjun , Wang Bingyin
Published: July 2023

Background

Early myocardial calcifications secondary to fulminant myocarditis (FM) are rare, and their natural evolution and effects on cardiac function are poorly understood. Here, we followed the patient for 4 years to observe the development of cardiac calcification and its impact on heart function.

Case summary

A 16-year-old man was hospitalized with a fever and cough for 1 day. The patient was previously healthy and had no history of heart disease or specific family conditions. The patient was positive for anti-Epstein–Barr virus IgG and IgM. The computed tomography (CT) scan showed no coronary lesions. Cardiogenic shock and recurrent ventricular fibrillation developed on the third day after admission, and the patient received rescue therapy such as endotracheal intubation, defibrillation, extracorporeal membrane oxygenation, and corticosteroids. On the 13th day of admission, a CT scan revealed significant calcification in the left ventricular wall. The patient was discharged after 30 days in the hospital. After discharge, his left ventricular calcification peaked at 6 months and gradually subsided after that, and his left ventricular function slowly returned to normal at 12 months.

Discussion

In younger patients, myocardial calcifications secondary to FM may occur as early as 13 days and affect cardiac function. After proper treatment and rehabilitation, the patient’s myocardial calcification can gradually subside and the cardiac function can gradually recover. For FM patients, timely and comprehensive intensive treatment, including heart, lung, and kidney replacement therapy and early administration of hormone preparations, may be beneficial to the early recovery of patients.
Diagnostic and therapeutic pathways for the malignant left atrial appendage: European Heart Rhythm Association physician survey
Authors: Anic Ante , Bakovic Darija , Jurisic Zrinka , Farkowski Michal , Lisica Lucija , Breskovic Toni , Nielsen-Kudsk Jens Erik , Perrotta Laura , de Asmundis Carlo , Boveda Serge , Chun Julian
Published: July 2023

Aims

Patients with atrial fibrillation who despite taking oral anti-coagulant therapy (OAT) suffer a stroke or systemic embolism (SSE) without vascular cause or who develop left atrial appendage (LAA) thrombus (LAAT) should be considered as having malignant LAA. The optimal treatment strategy to reduce SSE risk in such patients is unknown. The aim of the study is to investigate the diagnostic and therapeutic pathways for malignant LAA practiced in European cardiac centres.

Methods and results

An 18-item online questionnaire on malignant LAA was disseminated by the European Heart Rhythm Association (EHRA) Scientific Initiatives Committee. A total of 196 physicians participated in the survey. There seems to be high confidence in transoesophageal echocardiography (TEE) imaging, considering LAAT diagnosis. Switching to another direct oral anti-coagulant (DOAC) is the preferred initial step for the treatment of malignant LAA followed by a switch to vitamin K antagonist (VKA), low-molecular-weight heparin, or continued/optimized DOAC dosage, whereas LAA closure is the last option. Left atrial appendage closure is a viable option in patients with embolic stroke despite OAT and no evidence of thrombus at TEE (empty LAA) after comprehensive diagnostic measures to exclude other sources of embolism.

Conclusion

This EHRA survey provides a snapshot of the contemporary management of patients diagnosed with malignant LAA. Currently, the majority of patients are treated on an outpatient basis with either shifting from VKA to DOAC or from one DOAC to another. Left atrial appendage closure in this population seems to be reserved for patients with higher bleeding risk or complications of malignant LAA, such as stroke.
The Protective Effect of Familial Longevity Persists After Age 100: Findings From the Danish National Registers
Authors: Galvin Angéline , Pedersen Jacob Krabbe , Wojczynski Mary K , Ukraintseva Svetlana , Arbeev Konstantin , Feitosa Mary , Province Michael A , Christensen Kaare
Published: July 2023

Background

A recent study suggested that the protective effect of familial longevity becomes negligible for centenarians. However, the authors assessed the dependence on familial longevity in centenarians by comparing centenarians with 1 parent surviving to age 80+ to centenarians whose same-sexed parent did not survive to age 80. Here we test whether the protective effect of familial longevity persists after age 100 using more restrictive definitions of long-lived families.

Methods

Long-lived sibships were identified through 3 nationwide, consecutive studies in Denmark, including families with either at least 2 siblings aged 90+ or a Family Longevity Selection Score (FLoSS) above 7. Long-lived siblings enrolled in these studies and who reached age 100 were included. For each sibling, 5 controls matched on sex and year of birth were randomly selected among centenarians in the Danish population. Survival time from age 100 was described with Kaplan–Meier curves for siblings and controls separately. Survival analyses were performed using stratified Cox proportional hazards models.

Results

A total of 340 individuals from long-lived sibships who survived to age 100 and 1 700 controls were included. Among the long-lived siblings and controls, 1 650 (81%) were women. The results showed that long-lived siblings presented better overall survival after age 100 than sporadic long-livers (hazard ratio [HR]  = 0.80, 95% confidence interval [CI]  = 0.71–0.91), with even lower estimate (HR = 0.65, 95% CI = 0.50–0.85) if familial longevity was defined by FLoSS.

Conclusions

The present study, with virtually no loss to follow-up, demonstrated a persistence of protective effect of familial longevity after age 100.
“Ọmụgwọ” As Unpaid Labor? The Perceptions of Postpartum Caregiving Among Older Grandmothers in Southeast Nigeria
Authors: Iwuagwu Anthony Obinna
Published: July 2023

Background and Objectives

In Nigeria and many Sub-Saharan African countries where the majority are poor and cannot afford formal postpartum care, nursing mothers rely primarily on their mothers or older female relatives for postpartum care. Despite their invaluable contributions, such grandmothers often operate in a reality of inadequate social and institutional support. Yet, little is known about how women perceive this form of traditional care in Sub-Saharan Africa. This study explored the views of older grandmothers in Southeast Nigeria about postpartum caregiving, called “Ọmụgwọ.”

Research Design and Methods

Using a qualitative descriptive inquiry, the author employed criterion-purposive sampling and snowballing to recruit 17 older grandmothers who participated in the interviews, and data were analyzed in themes.

Results

Three themes and eight subthemes emerged. The themes cover perceptions supporting the continuity of Ọmụgwọ practice irrespective, the influence of culture on Ọmụgwọ practice, and the indirect rewards of the practice.

Discussion and Implications

The findings of this study could potentially influence postpartum caregiving policies for female older adults in Sub-Saharan Africa and further advance the quality of informal care during postpartum periods in Africa.
Exploiting image logs to reduce drilling hazards: an innovative Artificial Intelligence methodology applied in East Africa
Authors: Molossi Attilio , Pipan Michele
Published: July 2023

Image logs are crucial for petrophysical and structural characterization of drilled formations. Logging while drilling (LWD) image logs allow near real-time characterization of formations during drilling. Interpretation time required by humans can become critical, as structural interpretation provides the most crucial information for decision-making steps with respect to drilling operations. An example of this occurred in a deepwater system of reservoirs in East Africa. During the drilling of some wells, drilling was interrupted by unexpected borehole stability issues observed in a mass transport deposit. Those problems can detrimentally affect operations by impacting the efficiency of drilling. Therefore, a procedure for the automation of LWD data analysis was developed aimed at reducing drilling risk associated with borehole stability. A workflow is proposed based on an innovative assortment of AI methodologies for automatic real-time interpretation of LWD image log, applied to density image logs. The goal is to mimic manual human dip picking, combining computer vision, numerical series analysis and machine learning. Computer vision techniques are applied to detect the main density contrasts, representing the most likely surfaces. Sharp contrasts in the image are then investigated by dynamic time warping for similarity analysis. Finally, the geological plane is defined as a regression plane passing through the most similar contrasts, and a surface confidence criterion is defined based on the homogeneity of contrast along the curve suggested by the regression. Feature identification by a geologist was used as benchmark for comparison and metrics. Accuracy is referred to the difference between apparent dip and azimuth of geological surfaces coming from human and automated workflows, following the idea that two similar geometric results would eventually lead to equally similar geological considerations, and thus to similar operational measures. In general, a prediction accuracy of 60 per cent for the tested wells is observed, considering the total set of surfaces coming from the model. Nevertheless, the results suggest a positive correlation between the apparent dip of the discontinuities and the model error and a general less confidence for the surfaces with greater dip. By isolating the subset of low dipping features generated by the model, that is up to 35°, the accuracy appears to increase up to more than 70 per cent, suggesting that correlation is more difficult for high dipping geological planes. This class of curves also shows a general lower confidence and much of this latter class of surfaces are more likely to be found in the depth interval in which borehole stability issues occurred.
Still no differences in the length or scope of primary and ambulatory care for Medicaid and commercial patients
Authors: Ku Leighton
Published: July 2023

Many seek to improve the quality of primary care in the United States, particularly for Medicaid patients. This paper revisits the question of whether Medicaid patients receive less primary care, such as the length or scope of services per visit, than commercial patients. Analyses of 2016–2019 National Ambulatory Medical Care Survey data, the most recent available, find there were no significant differences in the average length of ambulatory care visits, or of primary care visits in particular, between Medicaid and commercial care, nor differences in the scope, based on the number of diagnostic and treatment services, health education topics covered, or the number of medications prescribed in the visit. Only small differences were found for uninsured patients. The duration and scope of ambulatory and primary care visits were primarily related to the characteristics of patients, visits, and the physicians’ practices. To improve primary and ambulatory care for disadvantaged patients, it may be more important to focus on increasing access to care by reducing insurance and cost-related barriers and on broad-based efforts to improve quality.
Genomic data resolve long-standing uncertainty by distinguishing white marlin (Kajikia albida) and striped marlin (K. audax) as separate species
Authors: Mamoozadeh N R , Graves J E , Bealey R , Schratwieser J , Holdsworth J C , Ortega-Garcia S , McDowell J R
Published: July 2023

Large pelagic fishes are often broadly distributed and capable of long-distance movements. These factors can promote gene flow that makes it difficult to disentangle intra- vs. inter-specific levels of genetic differentiation. Here, we assess the relationship of two istiophorid billfishes, white marlin (Kajikia albida) and striped marlin (K. audax), presently considered sister species inhabiting separate ocean basins. Previous studies report levels of genetic differentiation between these species that are smaller than those observed among populations of other istiophorid species. To determine whether white marlin and striped marlin comprise separate species or populations of a single globally distributed species, we surveyed 2520 single nucleotide polymorphisms (SNPs) in 62 white marlin and 242 striped marlin across the Atlantic, Pacific, and Indian oceans. Multivariate analyses resolved white marlin and striped marlin as distinct groups, and a species tree composed of separate lineages was strongly supported over a single lineage tree. Genetic differentiation between white marlin and striped marlin (FST = 0.5384) was also substantially larger than between populations of striped marlin (FST = 0.0192–0.0840), and we identified SNPs that allow unambiguous species identification. Our findings indicate that white marlin and striped marlin comprise separate species, which we estimate diverged at approximately 2.38 Mya.
Upper and/or Lower Respiratory Tract Infection Caused by Human Metapneumovirus After Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Piñana Jose Luis , Tridello Gloria , Xhaard Aliénor , Wendel Lotus , Montoro Juan , Vazquez Lourdes , Heras Inmaculada , Ljungman Per , Mikulska Malgorzata , Salmenniemi Urpu , Perez Ariadna , Kröger Nicolaus , Cornelissen Jan , Sala Elisa , Martino Rodrigo , Geurten Claire , Byrne Jenny , Maertens Johan , Kerre Tessa , Martin Murray , Pascual Maria Jesús , Yeshurun Moshe , Finke Jürgen , Groll Andreas H , Shaw Peter J , Blijlevens Nicole , Arcese William , Ganser Arnold , Suarez-Lledo Maria , Alzahrani Mohsen , Choi Goda , Forcade Edouard , Paviglianiti Annalisa , Solano Carlos , Wachowiak Jacek , Zuckerman Tsila , Bader Peter , Clausen Johannes , Mayer Jiri , Schroyens Wilfried , Metafuni Elisabetta , Knelange Nina , Averbuch Dina , de la Camara Rafael
Published: July 2023

Background

Human metapneumovirus (hMPV) epidemiology, clinical characteristics and risk factors for poor outcome after allogeneic stem cell transplantation (allo-HCT) remain a poorly investigated area.

Methods

This retrospective multicenter cohort study examined the epidemiology, clinical characteristics, and risk factors for poor outcomes associated with human metapneumovirus (hMPV) infections in recipients of allo-HCT.

Results

We included 428 allo-HCT recipients who developed 438 hMPV infection episodes between January 2012 and January 2019. Most recipients were adults (93%). hMPV infections were diagnosed at a median of 373 days after allo-HCT. The infections were categorized as upper respiratory tract disease (URTD) or lower respiratory tract disease (LRTD), with 60% and 40% of cases, respectively. Patients with hMPV LRTD experienced the infection earlier in the transplant course and had higher rates of lymphopenia, neutropenia, corticosteroid use, and ribavirin therapy. Multivariate analysis identified lymphopenia and corticosteroid use (>30 mg/d) as independent risk factors for LRTD occurrence. The overall mortality at day 30 after hMPV detection was 2% for URTD, 12% for possible LRTD, and 21% for proven LRTD. Lymphopenia was the only independent risk factor associated with day 30 mortality in LRTD cases.

Conclusions

These findings highlight the significance of lymphopenia and corticosteroid use in the development and severity of hMPV infections after allo-HCT, with lymphopenia being a predictor of higher mortality in LRTD cases.
Unmet need for contraception among women in Benin: a cross-sectional analysis of the Demographic and Health Survey
Authors: Yeboah Paa Akonor , Adzigbli Leticia Akua , Atsu Priscilla , Ansong-Aggrey Samuel Kwabena , Adu Collins , Cadri Abdul , Aboagye Richard Gyan
Published: July 2023

Background

The aim of the current study was to examine the prevalence and predictors of unmet need for contraception among women in sexual unions in Benin.

Methods

Data for the study was extracted from the recent 2017–2018 Benin Demographic and Health Survey. A weighted sample of 9513 women of reproductive age was included in the study. We used multivariable multilevel binary logistic regression analysis to examine the factors associated with unmet need for contraception.

Results

The prevalence of unmet need for contraception was 38.0% (36.7, 39.2). The odds of unmet need for contraception was higher among women with ≥4 births compared with those with no births, and among those who reported that someone else or others usually made decisions regarding their healthcare compared with those who make their own healthcare decisions. Wealth index was associated with a higher likelihood of unmet need for contraception. Also, the region of residence was associated with unmet need for contraception, with the highest odds being among women from the Mono region (adjusted odds ratio [aOR]=2.18, 95% CI 1.33 to 3.58).

Conclusions

Our study shows that the unmet need for contraception among women in Benin is relatively high. Our findings call on relevant stakeholders, including government and non-governmental organisations, to enhance women's empowerment as part of interventions that seek to prioritise contraceptive services for women.
Fatal concentrations of antidepressant and antipsychotic drugs in postmortem femoral blood
Authors: Kriikku Pirkko , Ojanperä Ilkka
Published: July 2023

Antidepressants and antipsychotics are both an important class of prescription drugs within postmortem (PM) toxicology because most of the substances are toxic in overdose and the mental disorders being treated may be associated with suicidality. A wide range of antidepressants and antipsychotics are currently included in up-to-date PM toxicology analysis protocols. However, apart from case studies, few reports on fatal concentrations based on large number of cases have been published in the literature. Based on PM investigations in Finland between 2000 and 2020, this study provides fatal reference concentrations in poisonings due to an antidepressant or an antipsychotic drug assigned as the principal intoxicant. Summary statistics for drug concentrations in PM femoral blood (min, max, mean, 10th, 25th, 50th, 75th, 90th percentile) were calculated for 17 antidepressant (N = 2,007) and for 12 antipsychotic drugs (N = 1,161). The proportion of suicide, accident and undetermined manner of death is indicated for each drug. Further, the fatal concentrations obtained in this study were evaluated by comparison with fatal and “normal” PM concentrations reported by two previously published approaches, the grouped causes of death approach and the all causes of death approach, respectively. This study shows that, despite the well-known variation in PM drug concentrations, competently generated fatal concentration results for the drugs studied are consistent to such an extent that they can be used as a reference in the interpretation process.
Emerging Roles of Gut Serotonin in Regulation of Immune Response, Microbiota Composition and Intestinal Inflammation
Authors: Grondin Jensine A , Khan Waliul I
Published: July 2023

Although the exact etiology of inflammatory bowel diseases (IBD) is unknown, studies have shown that dysregulated immune responses, genetic factors, gut microbiota, and environmental factors contribute to their pathogenesis. Intriguingly, serotonin (5-hydroxytryptamine or 5-HT) seems to be a molecule with increasingly strong implications in the pathogenesis of intestinal inflammation, affecting host physiology, including autophagy and immune responses, as well as microbial composition and function. 5-HT may also play a role in mediating how environmental effects impact outcomes in IBD. In this review, we aim to explore the production and important functions of 5-HT, including its impact on the gut. In addition, we highlight the bidirectional impacts of 5-HT on the immune system, the gut microbiota, and the process of autophagy and how these effects contribute to the manifestation of intestinal inflammation. We also explore recent findings connecting 5-HT signalling and the influence of environmental factors, particularly diet, in the pathogenesis of IBD. Ultimately, we explore the pleiotropic effects of this ancient molecule on biology and health in the context of intestinal inflammation.
Regulation of plant immunity via small RNA-mediated control of NLR expression
Authors: López-Márquez Diego , Del-Espino Ángel , Ruiz-Albert Javier , Bejarano Eduardo R , Brodersen Peter , Beuzón Carmen R
Published: July 2023

Plants use different receptors to detect potential pathogens: membrane-anchored pattern recognition receptors (PRRs) activated upon perception of pathogen-associated molecular patterns (PAMPs) that elicit pattern-triggered immunity (PTI); and intracellular nucleotide-binding leucine-rich repeat proteins (NLRs) activated by detection of pathogen-derived effectors, activating effector-triggered immunity (ETI). The interconnections between PTI and ETI responses have been increasingly reported. Elevated NLR levels may cause autoimmunity, with symptoms ranging from fitness cost to developmental arrest, sometimes combined with run-away cell death, making accurate control of NLR dosage key for plant survival. Small RNA-mediated gene regulation has emerged as a major mechanism of control of NLR dosage. Twenty-two nucleotide miRNAs with the unique ability to trigger secondary siRNA production from target transcripts are particularly prevalent in NLR regulation. They enhance repression of the primary NLR target, but also bring about repression of NLRs only complementary to secondary siRNAs. We summarize current knowledge on miRNAs and siRNAs in the regulation of NLR expression with an emphasis on 22 nt miRNAs and propose that miRNA and siRNA regulation of NLR levels provides additional links between PTI and NLR defense pathways to increase plant responsiveness against a broad spectrum of pathogens and control an efficient deployment of defenses.
Non-climacteric fruit development and ripening regulation: ‘the phytohormones show’
Authors: Perotti María Florencia , Posé David , Martín-Pizarro Carmen
Published: July 2023

Fruit ripening involves numerous physiological, structural, and metabolic changes that result in the formation of edible fruits. This process is controlled at different molecular levels, with essential roles for phytohormones, transcription factors, and epigenetic modifications. Fleshy fruits are classified as either climacteric or non-climacteric species. Climacteric fruits are characterized by a burst in respiration and ethylene production at the onset of ripening, while regulation of non-climacteric fruit ripening has been commonly attributed to abscisic acid (ABA). However, there is controversy as to whether mechanisms regulating fruit ripening are shared between non-climacteric species, and to what extent other hormones contribute alongside ABA. In this review, we summarize classic and recent studies on the accumulation profile and role of ABA and other important hormones in the regulation of non-climacteric fruit development and ripening, as well as their crosstalk, paying special attention to the two main non-climacteric plant models, strawberry and grape. We highlight both the common and different roles of these regulators in these two crops, and discuss the importance of the transcriptional and environmental regulation of fruit ripening, as well as the need to optimize genetic transformation methodologies to facilitate gene functional analyses.
TLK1-mediated RAD54 phosphorylation spatio-temporally regulates Homologous Recombination Repair
Authors: Ghosh Ishita , Kwon Youngho , Shabestari Aida Badamchi , Chikhale Rupesh , Chen Jing , Wiese Claudia , Sung Patrick , De Benedetti Arrigo
Published: July 2023

Environmental agents like ionizing radiation (IR) and chemotherapeutic drugs can cause severe damage to the DNA, often in the form of double-strand breaks (DSBs). Remaining unrepaired, DSBs can lead to chromosomal rearrangements, and cell death. One major error-free pathway to repair DSBs is homologous recombination repair (HRR). Tousled-like kinase 1 (TLK1), a Ser/Thr kinase that regulates the DNA damage checkpoint, has been found to interact with RAD54, a central DNA translocase in HRR. To determine how TLK1 regulates RAD54, we inhibited or depleted TLK1 and tested how this impacts HRR in human cells using a ISce-I-GR-DsRed fused reporter endonuclease. Our results show that TLK1 phosphorylates RAD54 at three threonines (T41, T59 and T700), two of which are located within its N-terminal domain (NTD) and one is located within its C-terminal domain (CTD). Phosphorylation at both T41 and T59 supports HRR and protects cells from DNA DSB damage. In contrast, phosphorylation of T700 leads to impaired HRR and engenders no protection to cells from cytotoxicity and rather results in repair delay. Further, our work enlightens the effect of RAD54-T700 (RAD54-CTD) phosphorylation by TLK1 in mammalian system and reveals a new site of interaction with RAD51.
Mitochondrial haplotype mutation alleviates respiratory defect of MELAS by restoring taurine modification in tRNA with 3243A > G mutation
Authors: Ueda Saori , Yagi Mikako , Tomoda Ena , Matsumoto Shinya , Ueyanagi Yasushi , Do Yura , Setoyama Daiki , Matsushima Yuichi , Nagao Asuteka , Suzuki Tsutomu , Ide Tomomi , Mori Yusuke , Oyama Noriko , Kang Dongchon , Uchiumi Takeshi
Published: July 2023

The 3243A > G in mtDNA is a representative mutation in mitochondrial diseases. Mitochondrial protein synthesis is impaired due to decoding disorder caused by severe reduction of 5-taurinomethyluridine (τm5U) modification of the mutant mt-tRNALeu(UUR) bearing 3243A > G mutation. The 3243A > G heteroplasmy in peripheral blood reportedly decreases exponentially with age. Here, we found three cases with mild respiratory symptoms despite bearing high rate of 3243A > G mutation (>90%) in blood mtDNA. These patients had the 3290T > C haplotypic mutation in addition to 3243A > G pathogenic mutation in mt-tRNALeu(UUR) gene. We generated cybrid cells of these cases to examine the effects of the 3290T > C mutation on mitochondrial function and found that 3290T > C mutation improved mitochondrial translation, formation of respiratory chain complex, and oxygen consumption rate of pathogenic cells associated with 3243A > G mutation. We measured τm5U frequency of mt-tRNALeu(UUR) with 3243A > G mutation in the cybrids by a primer extension method assisted with chemical derivatization of τm5U, showing that hypomodification of τm5U was significantly restored by the 3290T > C haplotypic mutation. We concluded that the 3290T > C is a haplotypic mutation that suppresses respiratory deficiency of mitochondrial disease by restoring hypomodified τm5U in mt-tRNALeu(UUR) with 3243A > G mutation, implying a potential therapeutic measure for mitochondrial disease associated with pathogenic mutations in mt-tRNAs.
Updated systematic review and meta-analysis of extended adjuvant temozolomide in patients with newly diagnosed glioblastoma
Authors: Gupta Tejpal , Selvarajan Jeevi Mona Priyadharshni , Kannan Sadhana , Menon Nandini , Dasgupta Archya , Chatterjee Abhishek
Published: July 2023

Background

Contemporary standard-of-care for newly diagnosed glioblastoma (GBM) is maximal safe resection followed by postoperative focal conformal radiotherapy (RT) plus concurrent temozolomide (TMZ) and 6-cycles of adjuvant TMZ (Stupp regimen). However, many patients continue to receive extended adjuvant TMZ (beyond 6-cycles) without solid scientific evidence. This review pools data from nonrandomized studies and randomized controlled trials (RCTs) comparing extended adjuvant TMZ (>6-cycles) to standard adjuvant TMZ (6-cycles) in patients with newly diagnosed GBM for updated evidence-synthesis.

Methods

This systematic review and meta-analysis was carried out in accordance with the Cochrane methodology including quality assessment of primary studies. Primary outcome of interest was comparative efficacy defined as progression-free survival (PFS) and overall survival (OS). Hazard ratios (HRs) for PFS and OS with corresponding 95% confidence interval (CIs) were extracted/computed from individual primary studies and pooled using random-effects model. Any p-value <0.05 was considered statistically significant.

Results

Evidence-synthesis was based on pooling of data from 2578 patients enrolled in 16 nonrandomized comparative studies and 5 RCTs. Overall, extended adjuvant TMZ was associated with statistically significant reduction in the risk of progression (HR = 0.72, 95%CI: 0.60–0.87; p = 0.007) and death (HR = 0.71, 95%CI: 0.57–0.90; p = 0.004) compared to standard adjuvant TMZ. However, on subgroup analysis, survival benefit of extended adjuvant TMZ was limited to data synthesized from retrospective nonrandomized comparative studies with no statistically significant difference in outcomes seen after pooling of data from RCTs only.

Conclusion

Apparent survival benefit of extended adjuvant TMZ in newly diagnosed GBM is largely driven by nonrandomized comparative studies with high inherent potential for multiple biases.
Platelet TLR7 is essential for the formation of platelet–neutrophil complexes and low-density neutrophils in lupus nephritis
Authors: Tay Sen Hee , Zharkova Olga , Lee Hui Yin , Toh Michelle Min Xuan , Libau Eshele Anak , Celhar Teja , Narayanan Sriram , Ahl Patricia Jennifer , Ong Wei Yee , Joseph Craig , Lim Jeffrey Chun Tatt , Wang Lingzhi , Larbi Anis , Liang Shen , Lateef Aisha , Akira Shizuo , Ling Lieng Hsi , Thamboo Thomas Paulraj , Yeong Joe Poh Seng , Lee Bernett Teck Kwong , Edwards Steven W , Wright Helen L , MacAry Paul Anthony , Connolly John E , Fairhurst Anna-Marie
Published: July 2023

Objectives

Platelets and low-density neutrophils (LDNs) are major players in the immunopathogenesis of SLE. Despite evidence showing the importance of platelet–neutrophil complexes (PNCs) in inflammation, little is known about the relationship between LDNs and platelets in SLE. We sought to characterize the role of LDNs and Toll-like receptor 7 (TLR7) in clinical disease.

Methods

Flow cytometry was used to immunophenotype LDNs from SLE patients and controls. The association of LDNs with organ damage was investigated in a cohort of 290 SLE patients. TLR7 mRNA expression was assessed in LDNs and high-density neutrophils (HDNs) using publicly available mRNA sequencing datasets and our own cohort using RT-PCR. The role of TLR7 in platelet binding was evaluated in platelet–HDN mixing studies using TLR7-deficient mice and Klinefelter syndrome patients.

Results

SLE patients with active disease have more LDNs, which are heterogeneous and more immature in patients with evidence of kidney dysfunction. LDNs are platelet bound, in contrast to HDNs. LDNs settle in the peripheral blood mononuclear cell (PBMC) layer due to the increased buoyancy and neutrophil degranulation from platelet binding. Mixing studies demonstrated that this PNC formation was dependent on platelet–TLR7 and that the association results in increased NETosis. The neutrophil:platelet ratio is a useful clinical correlate for LDNs, and a higher NPR is associated with past and current flares of LN.

Conclusions

LDNs sediment in the upper PBMC fraction due to PNC formation, which is dependent on the expression of TLR7 in platelets. Collectively, our results reveal a novel TLR7-dependent crosstalk between platelets and neutrophils that may be an important therapeutic opportunity for LN.
Fulfilling the Promise of RNA Therapies for Cardiac Repair and Regeneration
Authors: Giacca Mauro
Published: July 2023

The progressive appreciation that multiple types of RNAs regulate virtually all aspects of tissue function and the availability of effective tools to deliver RNAs in vivo now offers unprecedented possibilities for obtaining RNA-based therapeutics. For the heart, RNA therapies can be developed that stimulate endogenous repair after cardiac damage. Applications in this area include acute cardioprotection after ischemia or cancer chemotherapy, therapeutic angiogenesis to promote new blood vessel formation, regeneration to form new cardiac mass, and editing of mutations to cure inherited cardiac disease. While the potential of RNA therapeutics for all these conditions is exciting, the field is still in its infancy. A number of roadblocks need to be overcome for RNA therapies to become effective, in particular, related to the problem of delivering RNA medicines into the cells and targeting them specifically to the heart.
Fostering Community-Engaged Research on Criminal Legal Innovations with Logic Models
Authors: Epperson Matthew W , Guz Samantha , Sarantakos Sophia P
Published: July 2023

There is a persistent disconnect between research and practice, both in the social work profession as well as in the criminal legal system. Community-engaged research has been suggested as an approach to bridge this divide, but specific tools are needed to integrate research and practice efforts. This article presents three distinct logic model development processes that occurred in collaborative research and practice efforts in the context of criminal legal programming, including prosecutor-led diversion programs, a high-intensity drug court, and a multiagency justice and mental health collaborative. Logic model development incorporated multiple forms of program information using collaborative reflexivity, an approach focused on understanding the relationship between knowledge and power in the research process. For each program, the authors describe the context and process of logic model development, and how the logic models were used by both practitioners and researchers. The authors discuss how collaborative logic model development can facilitate community-engaged research, strengthen the research–practice connection, and advance applied social work scholarship.
Cardiac RGS7 and RGS11 drive TGFβ1‐dependent liver damage following chemotherapy exposure
Authors: Das Kiran , Basak Madhuri , Mahata Tarun , Biswas Sayan , Mukherjee Sukhes , Kumar Pranesh , Moniruzzaman Mahammed , Stewart Adele , Maity Biswanath
Published: July 2023

Off target damage to vital organ systems is an unfortunate side effect of cancer chemotherapy and remains a major limitation to the use of these essential drugs in the clinic. Despite decades of research, the mechanisms conferring susceptibility to chemotherapy driven cardiotoxicity and hepatotoxicity remain unclear. In the livers of patients with a history of chemotherapy, we observed a twofold increase in expression of G protein regulator RGS7 and a corresponding decrease in fellow R7 family member RGS11. Knockdown of RGS7 via introduction of RGS7 shRNA via tail vein injection decreased doxorubicin‐induced hepatic collagen and lipid deposition, glycogen accumulation, and elevations in ALT, AST, and triglycerides by approximately 50%. Surprisingly, a similar result could be achieved via introduction of RGS7 shRNA directly to the myocardium without impacting RGS7 levels in the liver directly. Indeed, doxorubicin‐treated cardiomyocytes secrete the endocrine factors transforming growth factor β1 (TGFβ1) and TGFβ superfamily binding protein follistatin‐related protein 1 (FSTL1). Importantly, RGS7 overexpression in the heart was sufficient to recapitulate the impacts of doxorubicin on the liver and inhibition of TGFβ1 signaling with the receptor blocker GW788388 ameliorated the effect of cardiac RGS7 overexpression on hepatic fibrosis, steatosis, oxidative stress, and cell death as well as the resultant elevation in liver enzymes. Together these data demonstrate that RGS7 controls both the release of TGFβ1 from the heart and the profibrotic and pro‐oxidant actions of TGFβ1 in the liver and emphasize the functional significance of endocrine cardiokine signaling in the pathogenesis of chemotherapy drive multiorgan damage.
Vimentin‐mediated myosin 10 aggregation at tips of cell extensions drives MT1‐MMP‐dependent collagen degradation in colorectal cancer
Authors: Ostrowska‐Podhorodecka Zofia , Ali Aiman , Norouzi Masoud , Ding Isabel , Abbasi Sevil , Arora Pamma D. , Wong Timothy H. F. , Magalhaes Marco , McCulloch Christopher A.
Published: July 2023

Colorectal cancer (CRC) is a high prevalence adenocarcinoma with progressive increases in metastasis‐related mortality, but the mechanisms governing the extracellular matrix (ECM) degradation important for metastasis in CRC are not well‐defined. We investigated a functional relationship between vimentin (Vim) and myosin 10 (Myo10), and whether this relationship is associated with cancer progression. We tested the hypothesis that Vim regulates the aggregation of Myo10 at the tips of cell extensions, which increases membrane‐type 1 matrix metalloproteinase (MT1‐MMP)‐associated local collagen proteolysis and ECM degradation. Analysis of CRC samples revealed colocalization of Vim with Myo10 and MT1‐MMP in cell extensions adjacent to sites of collagen degradation, suggesting an association with local cell invasion. We analyzed cultured CRC cells and fibroblasts and found that Vim accelerates aggregation of Myo10 at cell tips, which increases the cell extension rate. Vim stabilizes the interaction of Myo10 with MT1‐MMP, which in turn increases collagenolysis. Vim depletion reduced the aggregation of Myo10 at the cell extension tips and MT1‐MMP‐dependent collagenolysis. We propose that Vim interacts with Myo10, which in turn associates with MT1‐MMP to facilitate the transport of these molecules to the termini of cell extensions and there enhance cancer invasion of soft connective tissues.
Psychological Journey and Coping Styles of Parents of Infants With Biliary Atresia
Authors: Zhang Cheng-Lu , Wu Ying , Bao Ying , Jiang Wen-Yi , Hu Xiao-Jing
Published: July 2023

Background:

Biliary atresia is a rare and serious neonatal disease that affects the quality of life of both infants and parents. There is currently limited literature on the experiences of parents with infants diagnosed with biliary atresia.

Purpose:

To explore the psychological journey and coping styles of parents of infants with biliary atresia in a single center in Shanghai, China.

Methods:

A qualitative study design was used. Face-to-face and semistructured interviews were conducted with 10 parents of infants with biliary atresia. Colaizzi's method of data analysis was utilized, using NVivo 11.0 software.

Results:

The psychological journey and coping styles of parents could be divided into 4 stages. Different themes were extracted at different stages: before diagnosis, parents experienced complex emotions and actively sought treatment; at the diagnosis stage, negative emotions dominated and parents convinced themselves to accept reality; in the postoperative stage, positive emotions, accepting reality, active response, and the need to learn to take care of their infant gradually appeared; and at the discharge stage, parents accepted the coexistence of positive and negative emotions and the variety of needs that emerged.

Implications for Practice:

The findings of the study may help healthcare professionals identify and focus on the psychological needs of parents of infants with biliary atresia, leading them to implement effective coping strategies to increase the caregiving ability of parents.

Implications for Research:

Future research should explore the effects of supportive interventions for parents of infants with serious chronic illnesses.
Biomarker Signatures of Severe Acute Kidney Injury in a Critically Ill Cohort of COVID-19 and Non-COVID-19 Acute Respiratory Illness
Authors: Sathe Neha A. , Mostaghim Ana , Barnes Elizabeth , O’Connor Nicholas G. , Sahi Sharon K. , Sakr Sana S. , Zahlan Jana M. , Smith Craig H. , Fitzpatrick Michael , Morrell Eric D. , Liles W. Conrad , Bhatraju Pavan K.
Published: July 2023

IMPORTANCE:

Kidney and lung injury are closely inter-related during acute respiratory illness, but the molecular risk factors that these organ injuries share are not well defined.

OBJECTIVES:

We identified plasma biomarkers associated with severe acute kidney injury (AKI) during acute respiratory illness, and compared them to biomarkers associated with severe acute respiratory failure (ARF).

DESIGN, SETTINGS, AND PARTICIPANTS:

Prospective observational cohort study enrolling March 2020 through May 2021, at three hospitals in a large academic health system. We analyzed 301 patients admitted to an ICU with acute respiratory illness.

MAIN OUTCOMES AND MEASURES:

Outcomes were ascertained between ICU admission and day 14, and included: 1) severe AKI, defined as doubling of serum creatinine or new dialysis and 2) severe ARF, which included new or persistent need for high-flow oxygen or mechanical ventilation. We measured biomarkers of immune response and endothelial function, pathways related to adverse kidney and lung outcomes, in plasma collected within 24 hours of ICU admission. Severe AKI occurred in 48 (16%), severe ARF occurred in 147 (49%), and 40 (13%) patients experienced both. Two-fold higher concentrations of soluble tumor necrosis factor receptor-1 (sTNFR-1) (adjusted relative risk [aRR], 1.56; 95% CI, 1.24–1.96) and soluble triggering receptor on myeloid cells-1 (sTREM-1) (aRR, 1.85; 95% CI, 1.42–2.41), biomarkers of innate immune activation, were associated with higher risk for severe AKI after adjustment for age, sex, COVID-19, and Acute Physiology and Chronic Health Evaluation-III. These biomarkers were not significantly associated with severe ARF. Soluble programmed cell death receptor-1 (sPDL-1), a checkpoint pathway molecule, as well as soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular adhesion molecule-1 (sVCAM-1), molecules involved with endothelial-vascular leukocyte adhesion, were associated with both severe AKI and ARF.

CONCLUSIONS AND RELEVANCE:

sTNFR-1 and sTREM-1 were linked strongly to severe AKI during respiratory illness, while sPDL-1, sICAM-1 and sVCAM-1 were associated with both severe AKI and ARF. These biomarker signatures may shed light on pathophysiology of lung-kidney interactions, and inform precision medicine strategies for identifying patients at high risk for these organ injuries.
Comparison of Tumor Bed Delineation Using a Novel Radiopaque Filament Marker Versus Surgical Clips for Targeting Breast Cancer Radiotherapy
Authors: Shukla Utkarsh , Langner Ulrich W. , Linshaw David , Tan Sydney , Huber Kathryn E. , Miller Chelsea J. , Yu Esther , Leonard Kara L. , Sueyoshi Mark , Diamond Brett , Edmonson David , Wazer David E. , Gass Jennifer , Hepel Jaroslaw T.
Published: July 2023

Background:

Accuracy of tumor bed (TB) delineation is essential for targeting boost doses or partial breast irradiation. Multiple studies have shown high interobserver variability with standardly used surgical clip markers (CMs). We hypothesize that a radiopaque filament marker (FM) woven along the TB will improve TB delineation consistency.

Methods:

An FDA-approved FM was intraoperatively used to outline the TB of patients undergoing lumpectomy. Between January 2020 and January 2022, consecutive patients with FM placed after either (1) lumpectomy or (2) lumpectomy with oncoplastic reconstruction were identified and compared with those with CM. Six “experts” (radiation oncologists specializing in breast cancer) across 2 institutions independently defined all TBs. Three metrics (volume variance, dice coefficient, and center of mass [COM] deviation). Two-tailed paired samples t tests were performed to compare FM and CM cohorts.

Results:

Twenty-eight total patients were evaluated (14 FM and 14 CM). In aggregate, differences in volume between expert contours were 29.7% (SD ± 58.8%) with FM and 55.4% (SD ± 105.9%) with CM (P < 0.001). The average dice coefficient in patients with FM was 0.54 (SD ± 0.15), and with CM was 0.44 (SD ± 0.22) (P < 0.001). The average COM deviation was 0.63 cm (SD ± 0.53 cm) for FM and 1.05 cm (SD ± 0.93 cm) for CM; (P < 0.001). In the subset of patients who underwent lumpectomy with oncoplastic reconstruction, the difference in average volume was 21.8% (SD ± 20.4%) with FM and 52.2% (SD ± 64.5%) with CM (P<0.001). The average dice coefficient was 0.53 (SD ± 0.12) for FM versus 0.39 (SD ± 0.24) for CM (P < 0.001). The average COM difference was 0.53 cm (SD ± 0.29 cm) with FM versus 1.25 cm (SD ± 1.08 cm) with CM (P < 0.001).

Conclusion:

FM consistently outperformed CM in the setting of both standard lumpectomy and complex oncoplastic reconstruction. These data suggest the superiority of FM in TB delineation.
Similar Growth Outcomes in Children with Inflammatory Bowel Disease Initiated on Infliximab Originator or Biosimilar
Authors: McClinchie Madeline G. , Lakhani Alyshah , Abdel-Rasoul Mahmoud , McNicol Megan , Shkhkhalil Ala K. , Boyle Brendan B. , Maltz Ross M.
Published: July 2023

Background:

Growth is an important clinical outcome, especially in childhood-onset inflammatory bowel disease (IBD). Prior research has demonstrated growth improvements with infliximab therapy. There are limited studies evaluating whether clinical and growth outcomes in children initiated on the infliximab originator and infliximab biosimilar are similar.

Methods:

This was a single-center retrospective review of patients with IBD, younger than 17 years old, and initiated on the infliximab originator or biosimilar for at least 12 months between April 2016 and February 2021. Propensity score matching was utilized. Laboratory values, disease activity scores, and growth values were collected at baseline (prior to infliximab initiation), 6 months, and 12 months post initiation. Linear mixed models with random intercepts were used to test differences in measures over time and between study groups.

Results:

There were 113 patients on the originator and 39 patients on a biosimilar who met eligibility criteria. Propensity score methodology identified 37 dyads (1:1 match). Weight, height, and body mass index z scores increased over time (from baseline to 12 months) for both groups (P < 0.05) and there was a similar rate of change between study groups. Clinical outcomes of lab values (albumin, C-reactive protein, and hemoglobin) and disease activity scoring were similar from baseline to 12 months between study groups.

Conclusions:

There were similar improvements in growth and clinical outcomes in patients initiated on the infliximab originator compared to an infliximab biosimilar agent. This study adds to the limited research evaluating whether infliximab biosimilars have similar growth outcomes in children with IBD.
Effect of Peripherally Infused Norepinephrine on Reducing Central Venous Catheter Utilization
Authors: Powell Sara M. , Faust Andrew C. , George Stephy , Townsend Richard , Eubank Darla , Kim Richard
Published: July 2023

The purpose of this retrospective study was to evaluate the impact of peripherally administered norepinephrine on avoiding central venous catheter insertion while maintaining safety of the infusion. An institutional guideline allows peripheral infusion of norepinephrine via dedicated, 16- to 20-gauge, mid-to-upper arm intravenous (IV) catheters for up to 24 hours. The primary outcome was the need for central venous access in patients initially started on peripherally infused norepinephrine. A total of 124 patients were evaluated (98 initially on peripherally infused norepinephrine vs 26 with central catheter only administration). Thirty-six (37%) of the 98 patients who were started on peripheral norepinephrine avoided the need for central catheter placement, which was associated with $8,900 in direct supply cost avoidance. Eighty (82%) of the 98 patients who started peripherally infused norepinephrine required the vasopressor for ≤12 hours. No extravasation or local complications were observed in any of the 124 patients, regardless of site of infusion. Administration of norepinephrine via a dedicated peripheral IV site appears safe and may lead to a reduction in the need for subsequent central venous access. To achieve timely resuscitation goals, as well as to minimize complications associated with central access, initial peripheral administration should be considered for all patients.