bluuebunny/crossref_metadata_2025 huggingface dataset:
Navigating diagnostic options for inborn errors of immunity in children: a case-based illustration
Authors: Khan Yasmin W. , Minnicozzi Samantha C. , Lawrence Monica G.
Published: September 2022

Purpose of review

In recent years, there has been a dramatic increase in the number of recognized inborn errors of immunity (IEI), many of which present in childhood. This review discusses diagnostic approaches for some of the more common presentations of IEI in childhood.

Recent findings

Implementation of newborn screening (NBS) using the T cell receptor excision circle (TREC) assay has led to the timely identification of patients with severe combined immunodeficiency (SCID) as well as both syndromic and nonsyndromic forms of T cell lymphopenia, including DiGeorge syndrome. Improvements in the availability of immunophenotyping assays, genetic testing and advanced diagnostic techniques such as the artificial thymic organoid system can improve diagnostic clarity and impact management plans. Diagnostic improvements in humoral immunodeficiency include development of novel assays to quantify and functionally evaluate polysaccharide vaccine response.

IEI represent a rapidly growing field, particularly in paediatrics. Use of state-of-the-art diagnostic testing can facilitate rapid identification of IEI, hopefully allowing for initiation of prompt treatment and improved patient outcomes.
Measuring advanced motor skills in children with cerebral palsy: development of normative data and percentile curves for the Challenge-20 assessment
Authors: Milaščević Darko , Wright F. Virginia , Milošević Milan , Neubauer David
Published: September 2022

The Challenge-20 is an assessment of advanced motor skills of children with cerebral palsy. The purpose of this study was to develop age-related norms and percentile curves for the Challenge-20 with typically developing children (n = 150, 7 through 11 years), and compare Challenge-20 scores of independently ambulatory children with CP, Gross Motor Function Classification System level I (n = 135) and II (n = 56) to these age norms. Younger TD children (7 years) scored lowest, and older children (11 years) scored highest on the Challenge-20, showing similar developmental trajectories. Challenge-20 scores of 15% of children in GMFCS level I were situated above the lower 2.5th percentile curve of the typically developing children’s Challenge-20 growth curve, that is, overlapping into the typically developing child zone. The Challenge-20 is sensitive to the progression of advanced gross motor skills in typically developing children. Children with cerebral palsy, GMFCS I follow similar, albeit lower, Challenge score trajectory to that of typically developing children, and in some cases come close to lower level abilities of typically developing children. The reference values with typically developing children extend the Challenge-20‘s utility when assessing advanced gross motor skill of independently ambulatory children with cerebral palsy for physiotherapy intervention and physical activity planning and open the door to re-thinking more about advanced gross motor interventions for children with cerebral palsy in GMFCS levels I and II given their potential to progress along the developmental trajectory.
Nurse-Reported Staffing Guidelines and Exclusive Breast Milk Feeding
Authors: Lyndon Audrey , Simpson Kathleen Rice , Spetz Joanne , Zhong Jie , Gay Caryl L. , Fletcher Jason , Landstrom Gay L.
Published: September 2022

Background

Nursing care is essential to overall quality of healthcare experienced by patients and families—especially during childbearing. However, evidence regarding quality of nursing care during labor and birth is lacking, and established nurse-sensitive outcome indicators have limited applicability to maternity care. Nurse-sensitive outcomes need to be established for maternity care, and prior research suggests that the initiation of human milk feeding during childbirth hospitalization is a potentially nurse-sensitive outcome.

Objective

The aim of this study was to determine the relationship between nurse-reported staffing, missed nursing care during labor and birth, and exclusive breast milk feeding during childbirth hospitalization as a nurse-sensitive outcome.

Methods

2018 Joint Commission PC-05 Exclusive Breast Milk Feeding rates were linked to survey data from labor nurses who worked in a selected sample of hospitals with both PC-05 data and valid 2018 American Hospital Association Annual Survey data. Nurse-reported staffing was measured as the perceived compliance with Association of Women’s Health, Obstetric and Neonatal Nurses staffing guidelines by the labor and delivery unit. Data from the nurse survey were aggregated to the hospital level. Bivariate linear regression was used to determine associations between nurse and hospital characteristics and exclusive breast milk feeding rates. Generalized structural equation modeling was used to model relationships between nurse-reported staffing, nurse-reported missed care, and exclusive breast milk feeding at the hospital level.

Results

The sample included 184 hospitals in 29 states and 2,691 labor nurses who worked day, night, or evening shifts. Bivariate analyses demonstrated a positive association between nurse-reported staffing and exclusive breast milk feeding and a negative association between missed nursing care and exclusive breast milk feeding. In structural equation models controlling for covariates, missed skin-to-skin mother–baby care and missed breastfeeding within 1 hour of birth mediated the relationship between nurse-reported staffing and exclusive breast milk feeding rates.

Discussion

This study provides evidence that hospitals’ nurse-reported compliance with Association of Women’s Health, Obstetric and Neonatal Nurses staffing guidelines predicts hospital-exclusive breast milk feeding rates and that the rates are a nurse-sensitive outcome.
Brief Report: Intracellular Cystatin B Levels Are Altered in HIV-Infected Participants With Respect to Neurocognitive Status and Antiretroviral Therapy
Authors: Opsteen Skye , Moylan David , Taiwo Babafemi O. , Robertson Kevin R. , Overton E. Turner , Cutter Gary R. , Sabbaj Steffanie , Heath Sonya L. , Shacka John J.
Published: September 2022

With advances in HIV treatment, people with HIV (PWH) are living longer but experience aging-related comorbidities, including cognitive deficits, at higher rates than the general population. Previous studies have shown alterations in lysosomal proteins in blood from PWH with severe dementia. However, these markers have not been evaluated in PWH with milder neurocognitive impairment. We sought to determine whether levels of the lysosomal cysteine protease cathepsin B (CatB) and its endogenous inhibitor cystatin B (CysB) were altered in PWH with neurocognitive impairment and whether antiretroviral therapy (ART) further influenced these levels. Peripheral blood mononuclear cells were obtained from the tenofovir arm of a multicenter clinical trial in which ART-naive, HIV+ participants received treatment for 48 weeks (ACTG A5303, NCT01400412). PWH were divided by neurocognitive status (eg, with or without neurocognitive impairment) before ART initiation. Intracellular levels of CatB and CysB were measured in T cells and monocytes by means of flow cytometry. Levels of CysB were significantly decreased in both CD4+ T cells and CD8+ T cells after 48 weeks of ART in HIV+ participants without neurocognitive impairment but not in participants with neurocognitive impairment. Levels of CysB were increased in CD14+ monocytes from the participants with neurocognitive impairment after ART. Levels of CysB and CatB positively correlated regardless of HIV, neurocognitive status, or exposure to ART. These findings suggest that CysB has the potential to provide mechanistic insight into HIV-associated neurocognitive disorders or provide a molecular target for systemic monitoring or treatment of neurocognitive impairment in the context of ART and should be investigated further.
Association Between HIV and Prevalence and Manifestations of Asthma: Analysis of the Multicenter AIDS Cohort Study and Women's Interagency HIV Study
Authors: Drummond M. Bradley , Edmonds Andrew , Ramirez Catalina , Stosor Valentina , Barjaktarevic Igor Z. , Morris Alison , McCormack Meredith C. , Bhatt Surya P. , Alcaide Maria L. , Cribbs Sushma K. , D'Souza Gypsyamber , Bhandari Neha , Kunisaki Ken M. , Huang Laurence , Kassaye Seble G. , Foronjy Robert , Sharma Anjali , Westreich Daniel J. , Adimora Adaora A.
Published: September 2022

Background:

The association between HIV and asthma prevalence and manifestations remains unclear, with few studies including women.

Setting:

A retrospective observational cohort study from the Multicenter AIDS Cohort Study and Women's Interagency HIV Study.

Methods:

Asthma was defined in 2 ways: (1) self-report and (2) robust criteria requiring all the following: lack of fixed airflow obstruction, presence of wheeze on the St. George's Respiratory Questionnaire (SGRQ), and report of asthma therapies. Estimates of asthma prevalence and asthma-related manifestations were compared by HIV serostatus.

Results:

A total of 1815 men and 2122 women were included. Asthma prevalence did not differ between people with HIV (PWH) and people without HIV regardless of definition: self-report (men, 12.0% vs. 11.2%; women, 24.3% vs. 27.5%) and robust criteria (men, 5.0% vs. 3.4%; women, 12.8% vs. 13.2%). Among men with asthma, worse respiratory symptom burden was reported among those with HIV, regardless of asthma definition. Among women with self-reported asthma, those with HIV had less respiratory symptom burden. Regardless of serostatus, women with robust-defined asthma had similar respiratory symptoms across SGRQ domains and similar frequencies of phlegm, shortness of breath, and wheezing.

Conclusions:

Among PWH and people without HIV, asthma prevalence was 2-fold to 3-fold higher using self-reported definition rather than robust definition. In men and women, HIV was not associated with increased asthma prevalence. In men, HIV was associated with more respiratory symptoms when asthma was self-reported; the relationship was attenuated with the robust criteria. Further studies are needed to explore asthma phenotypes among PWH.
Laboratory Evaluation of the VISITECT Advanced Disease Semiquantitative Point-of-Care CD4 Test
Authors: Lechiile Kwana , Leeme Tshepo B. , Tenforde Mark W. , Bapabi Mbabi , Magwenzi Julita , Maithamako Oitshepile , Mulenga Fredah , Mohammed Terence , Ngidi Julia , Mokomane Margaret , Lawrence David S. , Mine Madisa , Jarvis Joseph N.
Published: September 2022

Background:

Advanced HIV disease (AHD; CD4 counts <200 cells/µL) remains common in many low- and middle-income settings. An instrument-free point-of-care test to rapidly identify patients with AHD would facilitate implementation of the World Health Organization (WHO) recommended package of care. We performed a laboratory-based validation study to evaluate the performance of the VISITECT CD4 Advanced Disease assay in Botswana.

Setting:

A laboratory validation study.

Methods:

Venous blood samples from people living with HIV having baseline CD4 testing in Gaborone, Botswana, underwent routine testing using flow cytometry, followed by testing with the VISITECT CD4 Advanced Disease assay by a laboratory scientist blinded to the flow cytometry result with a visual read to determine whether the CD4 count was below 200 cells/µL. A second independent investigator conducted a visual read blinded to the results of flow cytometry and the initial visual read. The sensitivity and specificity of the VISITECT for detection of AHD were determined using flow cytometry as a reference standard, and interrater agreement in VISITECT visual reads assessed.

Results:

One thousand fifty-three samples were included in the analysis. The VISITECT test correctly identified 112/119 samples as having a CD4 count <200 cells/µL, giving a sensitivity of 94.1% (95% confidence interval: 88.3% to 97.6%) and specificity of 85.9% (95% confidence interval: 83.5% to 88.0%) compared with flow cytometry. Interrater agreement between the 2 independent readers was 97.5%, Kappa 0.92 (P < 0.001).

Conclusions:

The VISITECT CD4 advanced disease reliably identified individuals with low CD4 counts and could facilitate implementation of the WHO recommended package of interventions for AHD.
Intraoral Approach to Fat Grafting Based on the Mimetic Muscle Unit
Authors: Kim Jin Woo , Lee Jae Hyun , Kim Yong Kyu
Published: September 2022

Background:

Recently, the concepts of anatomic-based fat grafting and mid-facial anatomy have been studied. However, there is no clear consensus on the optimal fat grafting technique. We aimed to introduce a novel intraoral approach to fat grafting based on mid-facial mimetic muscles, wherein a substantial amount of fat was injected into appropriate locations to increase patient satisfaction and decrease the need for additional surgical techniques.

Methods:

Sixty-four Asian women (mean age, 41.2 y) who had undergone fat grafting through the intraoral approach between 2014 and 2019 were enrolled. We sequentially performed the following steps: fat harvesting, centrifugation, and fat injection. All patients were followed at an outpatient clinic for 6 to 12 months. We obtained photographs of their face before and at 3 and 6 months postoperatively and conducted a 5-point scale questionnaire survey at the 2 time points postoperatively to evaluate the satisfaction of patients and surgeons. We divided the mid-facial areas into malar eminence, infraorbital, and nasolabial fold areas and evaluated the following items: volume consistency, softness, irregularity, and overall satisfaction.

Results:

Patients reported “satisfactory” for the postoperative results. There were only 2 cases of complication among the 64 cases which resolved spontaneously. The highest and lowest satisfaction were reported for the malar eminence and nasolabial fold areas, respectively.

Conclusions:

Fat grafting through the intraoral approach based on the mimetic muscle unit is an effective and safe method for mid-facial rejuvenation.
Draft genome sequences of Pseudomonas amygdali pv. loropetali pathotype strain DSM 105780 PT, isolated from Florida
Authors: Parajuli Apekshya , Harmon Carrie L. , Minsavage Gerald V. , Jones Debra D. , Timilsina Sujan , Paret Mathews L. , Jones Jeffrey B.
Published: September 2022

The pathogen that causes stem gall in Loropetalum chinense was first identified in Florida and Alabama in 2018 and named

Pseudomonas amygdali

pv. loropetali. We report the genome sequence of the pathotype strain of this pathogen,

Pseudomonas amygdali

pv. loropetali DSM105780 PT.
Estimating the performance of mass testing strategies for COVID-19: a case study for Costa Rica
Authors: Solís Maikol , Pasquier Carlos , Núñez-Corrales Santiago , Madrigal-Redondo Germán , Gatica-Arias Andrés
Published: September 2022

Devising effective mass testing strategies to control and suppress COVID-19 pandemic waves make up a complex sociotechnical challenge. It requires a trade-off between performing detection technologies in terms of specificity and sensitivity, and the availability and cost of individual tests per technology. Overcoming this trade-off requires first predicting the level of risk of exposure across the population available. Then selecting testing strategies that match resources to maximize positive case detection and optimize the number of tests and their total cost during sustained mass testing campaigns. In this article, we derive the behavior of four different mass testing strategies, grounded in guidelines and public health policies issued by the Costa Rican public healthcare system. We assume a (privacy-preserving) pre-classifier applied to patient data, Capable of partitioning suspected individuals into low-risk and high-risk groups. We consider the impact of three testing technologies, RT-qPCR, antigen-based testing and saliva-based testing (RT-LAMP). When available, we introduced a category of essential workers. Numerical simulation results confirm that strategies using only RT-qPCR tests cannot achieve sufficient stock capacity to provide efficient detection regardless of prevalence, sensitivity, or specificity. Strategies that harness the power of both pooling and RT-LAMP either maximize stock capacity or detection, efficiency, or both. Our work reveals that investing both in data quality and classification accuracy can improve the odds of achieving pandemic control and mitigation. Future work will concentrate, based on our findings, on constructing representative synthetic data through agent-based modeling and studying the properties of specific pre-classifiers under various scenarios.
The role of peripheral immunity in ALS: a population-based study
Authors: Grassano Maurizio , Manera Umberto , De Marchi Fabiola , Cugnasco Paolo , Matteoni Enrico , Daviddi Margherita , Solero Luca , Bombaci Alessandro , Palumbo Francesca , Vasta Rosario , Canosa Antonio , Salamone Paolina , Fuda Giuseppe , Casale Federico , Mazzini Letizia , Calvo Andrea , Moglia Cristina , Chiò Adriano
Published: September 2022

Background

Systemic inflammation has been proposed as a relevant mechanism in Amyotrophic Lateral Sclerosis (ALS). Recent evidence shows that an increased inflammatory status correlates with survival in ALS. Still, comprehensive data on ALS patients’ innate and adaptive immune responses and their effect on the clinical phenotype are lacking. Here, we investigate the role and characteristics of systemic immunity in a population-based ALS cohort using readily available hematological indexes that reflect changes in innate and adaptive immunity.

Methods

We collected the complete blood count (CBC) at diagnosis in ALS patients from the Piemonte and Valle d’Aosta Register for ALS (PARALS) from 2007 to 2019. Demographic and clinical data were collected using registry data. Leukocytes populations, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII) and lymphocyte-to-monocyte ratio (LMR) were derived from CBC. All variables were analyzed for association with clinical features in the entire cohort and then in sex- and age-based subgroups. Logistic, linear and Cox regression models were used as appropriate.

Results

After adjustment for relevant covariates, neutrophils (p=0.001) and markers of increased innate immunity (NLR, p=0.008 and SII, p=0.006) were associated with a faster disease progression. Similarly, elevated innate immunity markers correlated with worse pulmonary function and shorter survival. Sex-based differences emerged, as the prognosis in women also correlated with a low lymphocyte (p=0.045) and a decreased LMR (p=0.013). ALS patients with cognitive impairment exhibited lower levels of monocytes (p=0.0415) and, although only in later-onset ALS (age at onset > 70 years), lower lymphocytes (p=0.006) and increased NLR (p=0.021) and SII (p=0.030).

Conclusions and Relevance

Our results confirm that a dysregulated systemic immune system participates in ALS progression. More specifically, an elevated innate immune response is associated with faster progression and reduced survival. The immune response varied according to sex and age, thus prompting the speculation that involved immune pathways are patient-specific. Finally, we observed that ALS patients with greater cognitive impairment showed a reduction in monocytes count. Those data revealed that systemic inflammation plays a multifaceted role in ALS: further studies will help translate those findings into clinical practice or targeted treatments.
Effective connectivity of emotion and cognition under psilocybin
Authors: Stoliker Devon , Novelli Leonardo , Vollenweider Franz X. , Egan Gary F. , Preller Katrin H. , Razi Adeel
Published: September 2022

Classic psychedelics alter sense of self and patterns of self-related thought. These changes are hypothesised to underlie their therapeutic efficacy across internalising pathologies such as addiction and depression. Using resting-state functional MRI images from a randomised, double blinded, placebo-controlled clinical trial of 24 healthy adults under 0.215mg/kg psilocybin, we investigated how psilocybin modulates the effective connectivity between resting state networks and the amygdala that are involved in the appraisal and regulation of emotion and association with clinical symptoms. The networks included the default mode network (DMN), salience network (SN) and central executive network (CEN). Psilocybin decreased top-down effective connectivity from the resting state networks to the amygdala and decreased effective connectivity within the DMN and SN, while the within CEN effective connectivity increased. Effective connectivity changes were also associated with altered emotion and meaning under psilocybin. Our findings identify changes to cognitive-emotional connectivity associated with the subjective effects of psilocybin and the attenuation of the amygdala signal as a potential biomarker of psilocybin’s therapeutic efficacy.
The Relationship Between Symptoms and Job Loss among Japanese Workers During the COVID-19 Pandemic: A Prospective Cohort Study
Authors: Okahara Shintaro , Fujino Yoshihisa , Nagata Tomohisa , Kuwamura Mami , Mafune Kosuke , Muramatsu Keiji , Tateishi Seiichiro , Ogami Akira , Mori Koji ,   the CORoNaWork project
Published: September 2022

Objectives

The aim of this study was to clarify which workers’ symptoms led to unemployment during the COVID-19 pandemic.

Methods

This was a prospective cohort study using questionnaires about COVID-19 administered to Japanese workers. A baseline survey conducted in December 2020 was used to determine workers’ health history. Unemployment since the baseline survey was ascertained with a follow-up survey in December 2021. The odds ratios (ORs) of unemployment were estimated using a multilevel logistic model with adjusted covariates nested in prefecture of residence.

Results

Males (n= 8,682) accounted for 58.2% of the total sample (n= 14,910), and the mean age was 48.2 years. Multivariate analysis showed that workers with “pain-related problems,” “limited physical movement and mobility,” “fatigue, loss of strength or appetite, fever, dizziness, and moodiness,” “mental health problems,” or “sleep” had a greater probability of resigning for health reasons, resigning for all reasons other than retirement, and being unemployed. Those with “skin, hair, and cosmetic concerns” or “eye-related matters” had a greater probability of becoming unemployed.

Conclusions

We identified an association between workers’ symptoms and resignation or unemployment, with different symptoms having different ORs. Furthermore, there were differences in the associations among the effects of symptoms, work dysfunction, resignation/unemployment, and attitudes of others. Preventive interventions to help workers resolve or improve their symptoms could prevent their becoming unemployed or resigning.
Low Molecular Weight Hyaluronan Inhibits Lung Epithelial Ion Channels by Activating the Calcium-Sensing Receptor
Authors: Lazrak Ahmed , Song Weifeng , Yu Zhihong , Zhang Shaoyan , Nellore Anoma , Hoopes Charles W. , Woodworth Bradford A. , Matalon Sadis
Published: September 2022

Herein, we tested the hypothesis low molecular weight hyaluronan (LMW-HA) inhibits lung epithelial ion transport in-vivo, ex-vivo, and in-vitro by activating the calcium-sensing receptor (CaSR). Intranasal instillation of LMW-HA (150μg/ml) to C57BL/6 mice inhibited their alveolar fluid clearance (AFC) by 75%, increased the epithelial lining fluid (ELF) thickness threefold, and lung wet/dry (W/D) ratio by 20% 24hrs later. Incubation of lung slices from mouse and human lungs with 150μg/ml LMW-HA decreased the open probability (Po) of ENaC in ATII cell by more than 50% in 4hrs, inhibited amiloride sensitive short circuit current (SCC) 4hrs post exposure, and Cl−current through CFTR by more than 70%, and Na,K-ATPase current by 66% at 24hrs. In all cases the inhibitory effect of LMW-HA on lung epithelial ion transport in vivo, ex vivo, and in vitro preparations were reversed by the administration of 1μM of NPS2143, a CaSR inhibitor, or 150μg/ml HMW-HA. In HEK-293 cells co-transfected with CaSR and the calcium sensitive Cl−channel TMEM16-A, LMW-HA activated an inward Cl−current. These data are the first demonstration of the inhibitory effects of LMW-HA on lung epithelial ion and water transport, and are due to the activation of CaSR and its downstream signaling cascades.
Biologically relevant integration of transcriptomics profiles from cancer cell lines, patient-derived xenografts and clinical tumors using deep learning
Authors: Dimitrieva Slavica , Janssens Rens , Li Gang , Szalata Artur , Gopal Raja , Parmar Chintan , Kauffmann Audrey , Durand Eric Y.
Published: September 2022

Cell lines and patient-derived xenografts are essential to cancer research, however, the results derived from such models often lack clinical translatability, as these models do not fully recapitulate the complex cancer biology. It is critically important to better understand the systematic differences between cell lines, xenografts and clinical tumors, and to be able to identify pre-clinical models that sufficiently resemble the biological characteristics of clinical tumors across different cancers. On another side, direct comparison of transcriptional profiles from pre-clinical models and clinical tumors is infeasible due to the mixture of technical artifacts and inherent biological signals.

To address these challenges, we developed MOBER, Multi-Origin Batch Effect Remover method, to simultaneously extract biologically meaningful embeddings and remove batch effects from transcriptomic datasets of different origin. MOBER consists of two neural networks: conditional variational autoencoder and source discriminator neural network that is trained in adversarial fashion. We applied MOBER on transcriptional profiles from 932 cancer cell lines, 434 patient-derived tumor xenografts and 11’159 clinical tumors and identified pre-clinical models with greatest transcriptional fidelity to clinical tumors, and models that are transcriptionally unrepresentative of their respective clinical tumors. MOBER can conserve the biological signals from the original datasets, while generating embeddings that do not encode confounder information. In addition, it allows for transformation of transcriptional profiles of pre-clinical models to resemble the ones of clinical tumors, and therefore can be used to improve the clinical translation of insights gained from pre-clinical models. As a batch effect removal method, MOBER can be applied widely to transcriptomics datasets of different origin, allowing for integration of multiple datasets simultaneously.
Open spaced ridged hydrogel scaffolds containing TiSAMP surface chemistry promotes regeneration and recovery following spinal cord injury
Authors: Siddiqui Ahad M. , Thiele Fredric , Stewart Rachel , Rangnick Simone , Weiss Georgina , Chen Bingkun K. , Silvernail Jodi , Strickland Tammy , Nesbitt Jarred , Lim Kelly , Schwarzbauer Jean E. , Schwartz Jeffrey , Yaszemski Michael J. , Windebank Anthony J. , Madigan Nicolas N.
Published: September 2022

The spinal cord has poor ability to regenerate after injury, which may be due to cell loss, cyst formation, inflammation, and scarring. A promising approach to treat spinal cord injury (SCI) is the use of biomaterials. We have developed a novel hydrogel scaffold fabricated from oligo(poly(ethylene glycol) fumarate) (OPF) as a 0.08 mm thick sheet containing polymer ridges and a cell-attractive surface chemistry on the other side. When the cells are cultured on OPF with the chemical patterning, the cells attach, align, and deposit ECM along the direction of the pattern. Animals implanted with the rolled scaffold sheets had greater hindlimb recovery compared to the multichannel scaffold control, likely due to the greater number of axons growing across. Inflammation, scarring, and ECM deposits were equal across conditions. Overall, the results suggest that the scaffold sheets promote axon outgrowth that can be guided across the scaffold, thereby promoting hindlimb recovery.
Whole-body sorcin invalidation does not cause hypothalamic ER stress nor worsens obesity in C57BL/6 male mice fed a westernized diet
Authors: Parks Steven Z. , Rutter Guy A. , Leclerc Isabelle
Published: September 2022

Background

Soluble Resistance Related Calcium Binding Protein (sorcin) is a calcium (Ca2+) binding protein which has been shown to play a role in maintaining intracellular endoplasmic reticulum (ER) Ca2+ stores and lowering ER stress. Recently, our lab has demonstrated that sorcin expression was downregulated in the islets of Langerhans of mice fed a high-fat diet or in human islets incubated with the saturated fatty acid palmitate. We also showed that overexpression of sorcin under control of the rat insulin promoter (RIP7) in C57BL/6J mice, or whole body sorcin deletion in 129S1/SvImJ mice, improves or impairs insulin secretion and pancreatic β-cell function respectively. The mechanisms behind this beneficial role of sorcin in the pancreatic β-cell might depend on protection against lipotoxic endoplasmic reticulum (ER) stress through improved ER Ca2+ dynamics and activation of the Activating Transcription Factor 6 (ATF6) branch of the unfolded protein response (UPR). Whether sorcin is also implicated in hypothalamic ER stress during the progression of obesity is unknown. This could potentially contribute to the diminished satiety typically observed in overweight individuals.

Aim

To investigate a potential role of sorcin in hypothalamic ER stress, leptin resistance, hyperphagia and obesity.

Methods

Whole-body sorcin null mice, backcrossed onto the C57BL/6J genetic background, were used. Body weight, food intake and EchoMRI body composition were measured in vivo whereas qRT-PCR analysis of sorcin and ER stress markers expression were performed on the arcuate nucleus of the hypothalamus. Leptin signalling through STAT3 phosphorylation was measured by Western blots on sorcin-null HEK293 cells, engineered by CRISPR/Cas9, and transfected with leptin receptor (LepRb).

Results

Sorcin expression was not influenced in the arcuate nucleus (ARC) of the hypothalamus by diet-induced obesity. Whole-body sorcin ablation did not cause ARC ER stress nor changes in body weight, body composition or food intake in C57BL/6 male mice exposed to a high-fat, high-sugar diet. STAT3 phosphorylation (Y705) in response to leptin was not impaired in sorcin-null HEK293 cells.

Conclusion

In our model, whole body sorcin ablation did not increase hypothalamic ER stress nor influenced food intake or body weight.
Amount of Pannexin 1 in smooth muscle cells regulates sympathetic nerve induced vasoconstriction
Authors: Dunaway Luke S. , Billaud Marie , Macal Edgar , Good Miranda E. , Medina Christopher B. , Lorenz Ulrike , Ravichandran Kodi , Koval Michael , Isakson Brant E
Published: September 2022

Pannexin 1 (Panx1) forms high conductance channels that secrete ATP upon stimulation. The role of Panx1 in mediating constriction in response to direct sympathetic nerve stimulation is not known. Additionally, it is unknown how the expression level of Panx1 in SMCs influences a-adrenergic responses. We hypothesized that the amount of Panx1 in SMCs dictates the levels of sympathetic constriction and blood pressure. To test this hypothesis, we used genetically modified mouse models enabling expression of Panx1 in vascular cells to be varied. Genetic deletion of SMC Panx1 prevented constriction by electric field stimulation of sympathetic nerves. Conversely, over-expression of Panx1 in SMCs using a ROSA26 transgenic model increased sympathetic nerve-mediated constriction. Cx43 hemichannel inhibitors did not alter constriction. Next, we evaluated the effects of altered SMC Panx1 expression on blood pressure. To do this, we created mice combining a global Panx1 deletion, with ROSA26-Panx1 under the control of an inducible SMC specific Cre (Myh11). This resulted in mice that could express only human Panx1, only in SMCs. After tamoxifen, these mice had increased blood pressure that was acutely decreased by the Panx1 inhibitor spironolactone. Control mice genetically devoid of Panx1 did not respond to spironolactone. These data suggest Panx1 in SMCs could regulate the extent of sympathetic nerve constriction and blood pressure. The results also show the feasibility humanized Panx1-mouse models to test pharmacological candidates.
Expression Ratios of the Anti-Apoptotic BCL2 Family Members Dictate the Selective Addiction of KSHV-Transformed Primary Effusion Lymphoma Cell Lines to MCL1
Authors: Dunham Daniel , Viswanathan Prasanth , Gill Jackson , Manzano Mark
Published: September 2022

Kaposi’s sarcoma-associated herpesvirus (KSHV) causes several malignancies in people living with HIV, including primary effusion lymphoma (PEL). PEL cell lines exhibit oncogene addictions to both viral and cellular genes. Using CRISPR screens, we previously identified cellular oncogene addictions in PEL cell lines, including MCL1. MCL1 is a member of the BCL2 family, which functions to prevent intrinsic apoptosis and has been implicated in several cancers. Despite the overlapping functions of the BCL2 family members, PEL cells are only dependent on MCL1 suggesting that MCL1 may have non-redundant functions. To investigate why PEL cells exhibit selective addiction to MCL1, we inactivated the intrinsic apoptosis pathway by engineering BAX/BAK1 double knockout cells. In this context, PEL cells become resistant to MCL1 knockdown or MCL1 inactivation by the MCL1 inhibitor S63845, indicating that the main function of MCL1 in PEL cells is to prevent BAX/BAK1-mediated apoptosis. The selective requirement to MCL1 is due to MCL1 being expressed in excess over the BCL2 family. Ectopic expression of several BCL2 family proteins, as well as the KSHV BCL2 homolog, significantly decreased basal caspase 3/7 activity and buffered against staurosporine-induced apoptosis. Finally, over-expressed BCL2 family members can functionally substitute for MCL1, when it is inhibited by S63845. Together our data indicate that the expression levels of the BCL2 family likely explain why PEL tumor cells are highly addicted to MCL1. Importantly, our results suggest that caution should be taken when considering MCL1i as a monotherapy regimen for PEL, because resistance can easily develop.

IMPORTANCE

Primary effusion lymphoma (PEL) is caused by Kaposi’s sarcoma-associated herpesvirus. We previously showed that PEL cell lines require the anti-apoptotic protein MCL1 for survival, but not the other BCL2 family proteins. This selective dependence to MCL1 is unexpected as the BCL2 family functions similarly in preventing intrinsic apoptosis. Recently, new roles for MCL1 not shared with the BCL2 family have emerged. Here, we show that non-canonical functions of MCL1 are unlikely essential. Instead, MCL1 mainly functions to prevent apoptosis. The specific requirement to MCL1 is due to MCL1 being expressed in excess over the BCL2 family.

Consistent with this model, shifting these expression ratios changes the requirement away from MCL1 and towards the dominant BCL2 family gene. Together, our results indicate that although MCL1 is an attractive chemotherapeutic target to treat PEL, careful consideration must be taken as resistance to MCL1-specific inhibitors easily develops through BCL2 family overexpression.
HPV E6 upregulates MARCHF8 ubiquitin ligase and inhibits apoptosis by degrading the death receptors in head and neck cancer
Authors: Khalil Mohamed I. , Yang Canchai , Vu Lexi , Chadha Smriti , Welbon Craig , James Claire D. , Morgan Iain M. , Spanos William C. , Pyeon Dohun
Published: September 2022

The membrane-associated RING-CH-type finger ubiquitin ligase MARCHF8 is a human homolog of the viral ubiquitin ligases Kaposi’s sarcoma herpesvirus K3 and K5 that promote host immune evasion. Previous studies have shown that MARCHF8 ubiquitinates several immune receptors, such as the major histocompatibility complex II and CD86. While human papillomavirus (HPV) does not encode any ubiquitin ligase, the viral oncoproteins E6 and E7 are known to regulate host ubiquitin ligases. Here, we report that MARCHF8 expression is upregulated in HPV-positive head and neck cancer patients but not in HPV-negative head and neck cancer patients compared to normal individuals. MARCHF8 expression is highly upregulated by HPV oncoprotein E6-induced MYC/MAX transcriptional activation. The knockdown of MARCHF8 expression in human HPV-positive HNC cells restores cell surface expression of the tumor necrosis factor receptor superfamily (TNFRSF) death receptors, FAS, TRAIL-R1, and TRAIL-R2, and enhances apoptosis. MARCHF8 protein directly interacts with and ubiquitinates the TNFRSF death receptors. Further, MARCHF8 knockout in mouse oral cancer cells expressing HPV16 E6 and E7 augments cancer cell apoptosis and suppresses tumor growth in vivo. Our findings suggest that HPV inhibits host cell apoptosis by upregulating MARCHF8 and degrading TNFRSF death receptors in HPV-positive HNC cells.

IMPORTANCE

Since host cell survival is essential for viruses to replicate persistently, many viruses have evolved to prevent host cell apoptosis. The human papillomavirus (HPV) oncoproteins are known to dysregulate proapoptotic proteins. However, our understanding of detailed mechanisms for HPV to inhibit apoptosis is limited. Here, we report that HPV E6 induces transcription of the membrane-associated ubiquitin ligase MARCHF8, which is upregulated in HPV-positive head and neck cancer. MARCHF8 ubiquitinates the tumor necrosis factor receptor superfamily (TNFRSF) death receptors, FAS, TRAIL-R1, and TRAIL-R2 for degradation. We further revealed that downregulation of the death receptors by MARCHF8 prevents cancer cell apoptosis and that knockout of MARCHF8 expression significantly inhibits in vivo tumor growth and enhances tumor-free survival of mice transplanted with mouse oral cancer cells expressing HPV16 E6 and E7.These results suggest that virus-induced degradation of death receptors leads to cancer cell survival in HPV-positive head and neck cancer.
Disparities in research capacity for tobacco control: an inventory of peer-reviewed publications using the Global Tobacco Surveillance System data
Authors: de Quevedo Isabel Garcia , Marellapudi Amulya , Rainey Edward , Twentyman Evelyn
Published: September 2022

Peer-reviewed publications using tobacco surveillance data represent a critical step toward evidence-based tobacco control, but research and publication capacity in countries with fewer resources may be limited. This paper describes patterns in use of the Global Adult Tobacco Survey (GATS) and/or Global Youth Tobacco Survey (GYTS) data for publications, investigates the origin of the data versus the origin of lead authorship, and describes geographic patterns of publications by country, region, and country income. A bibliometric inventory using six search engines was conducted for relevant studies using data from either of these surveys between January 1999 and January 2021. Descriptive statistics, including frequencies and percentages,were used to analyze publication characteristics. Our search strategy retrieved 1,834 initial records; 493 publications were ultimately included: 249 (50.5%) used adult surveillance data (GATS) and 248 (50.3%) used youth surveillance data (GYTS). Most publications were in English (97.2%, n=479). Data published 50 or more times represented 12 low- and middle-income countries (LMIC): India, Bangladesh, Vietnam, Mexico, Egypt, Thailand, Poland, Philippines, China, Russian Federation, Turkey and Ukraine. While many of the papers analyzed data from low- and middle-income countries, the number of publications by origin of lead author was the highest for the United States (n=135) and India (n=84). Over 80% of the world’s 1.3 billion tobacco users live in low- and middle-income countries (LMIC) and we found underrepresentation of these countries as lead authors. These findings can be used to identify opportunities to enhance capacity for analysis, research and dissemination of global tobacco control data in LMIC.
Genetic and environmental etiology of the broad avoidant restrictive food intake disorder phenotype in 6- to-12-year-old Swedish twins
Authors: Dinkler Lisa , Lichtenstein Paul , Lundström Sebastian , Larsson Henrik , Micali Nadia , Taylor Mark J. , Bulik Cynthia M.
Published: September 2022

IMPORTANCE

Avoidant restrictive food intake disorder (ARFID) is characterized by an extremely limited range and/or amount of food eaten, resulting in the persistent failure to meet nutritional and/or energy needs. Its etiology is poorly understood and knowledge of genetic and environmental contributions to ARFID is needed to guide future research.

OBJECTIVE

To determine the extent to which genetic and environmental factors contribute to the liability to the broad ARFID phenotype.

DESIGN, SETTING, AND PARTICIPANTS

A nationwide Swedish twin cohort including 16,951 twin pairs born 1992-2010 whose parents participated in the Child and Adolescent Twin Study in Sweden (CATSS) at twin age 9 or 12 years (49.4% female). CATSS was linked to the National Patient Register (NPR) and the Prescribed Drug Register (PDR).

MAIN OUTCOME/MEASURES

From CATSS, NPR, and PDR, we extracted all parent-reports, diagnoses, procedures, and prescribed drugs between age 6 and 12 that were relevant to the DSM-5 ARFID criteria and developed a composite measure for the ARFID phenotype (i.e., avoidant/restrictive eating with clinically significant impact such as low weight or nutritional deficiency, and with fear of weight gain as an exclusion). In sensitivity analyses, we controlled for autism and medical conditions that could account for the eating disturbance. We fitted univariate liability threshold models to estimate the relative contribution of genetic and environmental variation to the liability to the ARFID phenotype.

RESULTS

We identified 667 children (2.0%, 38.2% female) with the ARFID phenotype between age 6 and 12. Variation in the liability to ARFID was largely explained by additive genetic factors (0.79, 95% confidence interval [CI] 0.71-0.86), with significant contributions from non-shared environmental factors (0.21, 95% CI 0.14-0.29). Heritability was very similar when excluding children with autism (0.77, 95% CI 0.67-0.84) or medical illnesses that could account for the eating disturbance (0.80, 95% CI 0.71-0.86).

CONCLUSIONS AND RELEVANCE

Prevalence and sex distribution of the broad ARFID phenotype were similar to previous studies, supporting the use of existing epidemiological data to identify ARFID. This first study of the genetic and environmental etiology of ARFID suggests that ARFID is highly heritable, encouraging future twin and molecular genetic studies.
Anemia among Pregnant Women in Cambodia: A Descriptive Analysis of Temporal and Geospatial Trends and Logistic Regression-Based Examination of Factors Associated with Anemia in Pregnant Women
Authors: Um Samnang , Sopheab Heng , Yom An , Muir Jonathan A.
Published: September 2022

Anemia is a major public health problem for thirty-two million pregnant women worldwide. Anemia during pregnancy is a leading cause of child low birth weight, preterm birth, and perinatal/neonatal mortality. Pregnant women are at higher risk of anemia due to micronutrient deficiencies, hemoglobinopathies, infections, socio-demographic and behavioral factors. This study aimed to: 1) assess temporal and geospatial trends of anemia in Cambodia and 2) identify factors associated with anemia among pregnant women aged 15-49 years old in Cambodia. We analyzed data from the Cambodia Demographic and Health Survey (CDHS) for 2005, 2010, and 2014. Data were pooled across the three survey years for all pregnant women aged 15-49 years. Survey weights were applied to account for the complex survey design of the CDHS. Descriptive statistics were estimated for key sociodemographic characteristics of the study population. We used logistic regressions to assess factors associated with anemia among pregnant women aged 15-49 years old. Anemia in pregnant women aged 15-49 in Cambodia decreased from 56% in 2005 to 53% in 2014. With the highest in Preah Vihear and Stung Treng provinces (74.3%), in Kratie province (73%), and in Prey Veng (65.4%) in 2005, 2010, and 2014 respectively. Compared to pregnant women from the wealthiest households, women from poorest households were more likely to have anemia (AOR = 2.8; 95% CI: 1.76-4.9). Pregnant women from coastal regions were almost twice as likely of having anemia (AOR = 1.9; 95% CI: 1.2-3.0). Pregnant women were more likely anemic if they were in their 2nd trimester (AOR = 2.6; 95% CI: 1.9-3.6) or 3rd trimester (AOR = 1.6 95% CI: 1.2-2.3). Anemia remains highly prevalent among pregnant women in Cambodia. Public health interventions and policies to alleviate anemia should be prioritized and shaped to address these factors
Estimating the health impacts of sugar-sweetened beverage tax for informing policy decisions about the obesity burden in Vietnam
Authors: Nguyen Duyen Thuy , Van Hoang Minh , Dao Son , Do Phuong Hong , Nguyen Quang Dinh , Jewell Jo , Amies-Cull Ben , Muthu Maharajan , Hoang Ly-Na , Le Thu Thi , Nguyen An Thi , Tran Bao Quoc , O’Neill Ciaran
Published: September 2022

Background

Considered a “best buy” intervention to cope with the obesity burden, a tax on sugar-sweetened beverages (SSBs) has been adopted in more than 40 countries. In Vietnam, a tax on SSBs has been proposed several times (most recently in 2017). This study aimed to estimate the health impacts of different SSBs tax plans currently under discussion to provide an evidence base to inform decision-making about a SSBs tax policy in Vietnam.

Method

Five tax scenarios were modelled, representing three levels of retail price increase: 5%, 11% and 19-20%. Scenarios of the highest price increase were assessed across three different tax designs: ad valorem, volume-based specific tax & sugar based specific tax. In each case we modelled SSBs consumption in each tax scenario; how this reduction in consumption translates to a reduction in total energy intake and how this relationship in turn translates to an average change in body weight and obesity status among adults by applying the calorie-to weight conversion factor. Changes in diabetes type 2 diabetes burden were then calculated based on the change in average body mass index of the modelled cohort. A Monte Carlo simulation approach was applied on the conversion factor of weight change and diabetes risk reduction for the sensitivity analysis.

Results

While the impact of a 5% price increase arising from a tax was relatively small, increasing SSBs’ price up to 20% appeared to impact substantially on overweight and obesity rates (reduction of 12.7% and 12.4% respectively) saving 27 million USD for direct medical cost. The greatest reduction in rates was observed for overweight (23≤BMI<25) and obesity grade 1 (25≤BMI<30). The decline in overweight and obesity rates was slightly higher for women than men. Differences were evident across all three tax designs with a specific tax based on sugar density achieving greatest effects.