bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of risk factors of treatment discontinuation among patients on paliperidone palmitate and risperidone microspheres in France, Germany and Belgium
Authors: Cai Rui , Decuypere Flore , Chevalier Pierre , Desseilles Martin , Lambert Martin , Fakra Eric , Wimmer Antonie , Guillon Pascal , Pype Stefan , Godet Annabelle , Borgmeier Valeria
Published: June 2022

Background

Long-acting antipsychotics (e.g. 1-monthly (PP1M) / 3-monthly (PP3M) injection forms of paliperidone palmitate) have been developed to improve treatment continuation in schizophrenia patients. We aim to assess risk factors of treatment discontinuation of patients on paliperidone palmitate and risperidone microsphere. Additionally, treatment discontinuation between patients with PP1M and PP3M was compared.

Methods

The IQVIA Longitudinal Prescription databases were used. Risk factors of treatment discontinuation were identified by a multilevel survival regression using Cox proportional hazards model. Kaplan Meier analyses were performed by identified significant risk factors.

Results

Twenty-five thousand three hundred sixty-one patients (France: 9,720; Germany: 14,461; Belgium: 1,180) were included. Over a one-year follow-up period, a significant lower treatment discontinuation was observed for patients newly initiated on paliperidone palmitate (53.8%) than those on risperidone microspheres (85.4%). Additionally, a significantly lower treatment discontinuation was found for ‘stable’ PP3M patients (19.2%) than ‘stable’ PP1M patients (37.1%). Patients were more likely to discontinue when drugs were prescribed by GP only (HR = 1.68, p < 0.001 vs. psychiatrist only) or if they were female (HR = 1.07, p < 0.001), whereas discontinuation decreased with age (31–50 years: HR = 0.95, p = 0.006 and > 50 years: HR = 0.91, p < 0.001 vs. 18–30 years).

Conclusions

This study demonstrates that patients stay significantly longer on treatment when initiated on paliperidone palmitate as compared to risperidone microspheres. It also indicated a higher treatment continuation of PP3M over PP1M. Treatment continuation is likely to be improved by empowering GPs with mental health knowledge and managing patients by a collaborative primary care-mental health model. Further research is needed to understand why females and younger patients have more treatment discontinuation.
What makes a perinatal woman suicidal? A grounded theory study
Authors: Reid Holly E. , Pratt Daniel , Edge Dawn , Wittkowski Anja
Published: June 2022

Background

Suicide is a leading cause of maternal death during pregnancy and up to a year after birth. Psychological and psychosocial risk factors for maternal suicide ideation and behaviour have been identified but do not account for why mothers begin to experience suicidal thoughts. Qualitative research offers a way of identifying what might drive mothers to initially consider suicide and then go on to act on such thoughts; crucial for the development of assessments to identify, and interventions to target, maternal suicide ideation and behaviour. We aimed to develop a grounded theory outlining what makes women think about suicide and/or engage in suicidal behaviour during pregnancy and the first 12 months following birth?

Method

Semi-structured interviews were conducted with 12 mothers in the UK who had suicidal thoughts during pregnancy and/or the first year following birth. A constructivist approach to grounded theory was adopted which guided the data collection and analysis processes.

Results

We developed a model outlining the theorised process of psychological factors that culminates in mothers experiencing suicidal thoughts and then making a suicide attempt during the perinatal period. The process was initiated when mothers felt attacked by motherhood which led to feeling like a failure, self-identifying as a “bad mother” and subsequent appraisals of entrapment and/or defeat. When nothing resolved the distress and as mothers collated reasons for why they perceived they needed to die, suicidal behaviour became a viable and appealing option. We theorised that mothers might make a suicide attempt when they entered a state of intense “darkness” brought on by a trigger, followed by a temporary lapse in the conflict between the desire to live and desire to die and an opportunity to attempt.

Conclusions

Participants stressed the rapid onset of suicidal thoughts. We suggest that healthcare professionals enquire about the mother’s feelings towards the baby and of isolation, how she views herself as a mother, feelings of entrapment and defeat during routine contacts to aid identification and prevention of suicidal ideation/behaviour. Suggested interventions to prevent suicidal thoughts and behaviour include helping women manage their expectations for pregnancy and the postpartum period.
Oxytocin receptor gene methylation as a molecular marker for severity of depressive symptoms in affective disorder patients
Authors: Ludwig Birgit , Carlberg Laura , Kienesberger Klemens , Swoboda Patrick , Swoboda Marleen M. M. , Bernegger Alexandra , Koller Romina , Inaner Michelle , Fuxjäger Monika , Zotter Melanie , Schmelzle Nicolas , Senft Birgit , Meisner Lisa , Fischer-Hansal Daniela , Huber Jasmin , Schoenthaler Silvia , Kapusta Nestor D. , Haslacher Helmuth , Aigner Martin , Weinhaeusel Andreas , Kasper Siegfried , Schosser Alexandra
Published: June 2022

Background

Oxytocin (OXT) is a neuropeptide and hormone involved in emotional functioning and also seems to play a role in moderating the stress response. Both preclinical and clinical studies point to an increased methylation status of the Oxytocin receptor (OXTR) promoter region with concomitant deficits in social, cognitive and emotional functioning. We hypothesize that methylation levels (%) of the oxytocin receptor promoter region correlate with the severity of depression symptoms and/or with the severity of childhood trauma within this present sample of affective disorder patients.

Methodology

Eight hundred forty six (846) affective disorder patients of Central European origin were recruited at the Department of Psychiatry and Psychotherapy of the Medical University Vienna, the Karl Landsteiner University for Health and Science and Zentren für seelische Gesundheit, BBRZ-Med Leopoldau. Psychiatric assessment included a semi-structured diagnostic interview (Schedules for Clinical Assessment in Neuropsychiatry), the Hamilton Depression Scale and the Childhood Trauma Questionnaire. Concomitantly DNA samples of peripheral blood cells were collected for Multiplexed and Sensitive DNA Methylation Testing.

Results

Our data suggests a positive but not significant association between OXTR promoter Exons 1–3 methylation levels and severity of depression symptoms as well as severity of emotional neglect in affective disorder patients and no association with childhood trauma.

Conclusions

Our findings contribute to elucidate the role of OXTR in affective disorders, but further longitudinal studies in particular are necessary to broaden the current state of knowledge.
Mediators of socioeconomic inequalities in preterm birth: a systematic review
Authors: McHale Philip , Maudsley Gillian , Pennington Andy , Schlüter Daniela K. , Barr Ben , Paranjothy Shantini , Taylor-Robinson David
Published: June 2022

Background

Rates of preterm birth are substantial with significant inequalities. Understanding the role of risk factors on the pathway from maternal socioeconomic status (SES) to preterm birth can help inform interventions and policy. This study therefore aimed to identify mediators of the relationship between maternal SES and preterm birth, assess the strength of evidence, and evaluate the quality of methods used to assess mediation.

Methods

Using Scopus, Medline OVID, “Medline In Process & Other Non-Indexed Citation”, PsycINFO, and Social Science Citation Index (via Web of Science), search terms combined variations on mediation, socioeconomic status, and preterm birth. Citation and advanced Google searches supplemented this. Inclusion criteria guided screening and selection of observational studies Jan-2000 to July-2020. The metric extracted was the proportion of socioeconomic inequality in preterm birth explained by each mediator (e.g. ‘proportion eliminated’). Included studies were narratively synthesised.

Results

Of 22 studies included, over one-half used cohort design. Most studies had potential measurement bias for mediators, and only two studies fully adjusted for key confounders. Eighteen studies found significant socioeconomic inequalities in preterm birth. Studies assessed six groups of potential mediators: maternal smoking; maternal mental health; maternal physical health (including body mass index (BMI)); maternal lifestyle (including alcohol consumption); healthcare; and working and environmental conditions. There was high confidence of smoking during pregnancy (most frequently examined mediator) and maternal physical health mediating inequalities in preterm birth. Significant residual inequalities frequently remained. Difference-of-coefficients between models was the most common mediation analysis approach, only six studies assessed exposure-mediator interaction, and only two considered causal assumptions.

Conclusions

The substantial socioeconomic inequalities in preterm birth are only partly explained by six groups of mediators that have been studied, particularly maternal smoking in pregnancy. There is, however, a large residual direct effect of SES evident in most studies. Despite the mediation analysis approaches used limiting our ability to make causal inference, these findings highlight potential ways of intervening to reduce such inequalities. A focus on modifiable socioeconomic determinants, such as reducing poverty and educational inequality, is probably necessary to address inequalities in preterm birth, alongside action on mediating pathways.
Exploratory insights into novel prehabilitative neuromuscular exercise-conditioning in total knee arthroplasty
Authors: Risso Anna Maria , van der Linden Marietta L. , Bailey Andrea , Gallacher Peter , Gleeson Nigel
Published: June 2022

Background

Contemporary strategies for prehabilitation and rehabilitation associated with total knee arthroplasty (TKA) surgery have focused on improving joint range-of-motion and function with less emphasis on neuromuscular performance beneficially affecting joint stability. Furthermore, prehabilitation protocols have been found to be too long and generic-in-effect to be considered suitable for routine clinical practice.

Methods

A pragmatic exploratory controlled trial was designed to investigate the efficacy of a novel, acute prehabilitative neuromuscular exercise-conditioning (APNEC) in patients electing TKA. Adults electing unilateral TKA were assessed and randomly allocated to exercise-conditioning (APNEC, n = 15) and usual care (Control, n = 14) from a specialised orthopaedic hospital, in the United Kingdom. APNEC prescribed nine stressful exercise-conditioning sessions for the knee extensors of the surgery leg, accrued over one week (3 sessions·week−1; 36 exercise repetitions in total; machine, gravity-loaded) and directly compared with usual care (no exercise). Prescribed exercise stress ranged between 60%—100% of participant’s daily voluntary strength capacity, encompassing purposefully brief muscular activations (≤ 1.5 s). Baseline and follow-up indices of neuromuscular performance focusing on muscle activation capacity (electromechanical delay [EMD], rate of force development [RFD] and peak force [PF]) were measured ipsilaterally using dynamometry and concomitant surface electromyography (m. rectus femoris[RF] and m. vastus lateralis[VL]).

Results

Group mean ipsilateral knee extensor muscular activation capacity (EMDRF [F(3,57) = 53.5; p < 0.001]; EMDVL [F(3,57) = 50.0; p < 0.001]; RFD [F(3,57) = 10.5; p < 0.001]) and strength (PF [F(3,57) = 16.4; p < 0.001]) were significantly increased following APNEC (Cohen’s d, 0.5—1.8; 15% to 36% vs. baseline), but unchanged following no exercise control (per protocol, group by time interaction, factorial ANOVA, with repeated measures), with significant retention of gains at 1-week follow-up (p < 0.001).

Conclusions

The exploratory APNEC protocol elicited significant and clinically-relevant improvement and its retention in neuromuscular performance in patients awaiting TKA.

Trial registration

(date and number): clinicaltrial.gov: NCT03113032 (4/04/2017) and ISRCTN75779521 (3/5/2017).
Long-term postoperative pneumonia in elderly patients with early gastric cancer
Authors: Kamiya Ayako , Hayashi Tsutomu , Sakon Ryota , Ishizu Kenichi , Wada Takeyuki , Otsuki Sho , Yamagata Yukinori , Katai Hitoshi , Yoshikawa Takaki
Published: June 2022

Background

Pneumonia is a major cause of death in the elderly population. Considering body weight loss, muscle loss, and reflux after gastrectomy, elderly patients are considered to be at very high risk for pneumonia, which could decrease overall survival because early gastric cancer is mostly curable only by surgery. We aimed to clarify the incidence of pneumonia in the long-term period after gastrectomy in elderly patients who were diagnosed with early gastric cancer and its risk factors.

Methods

We retrospectively examined patients of > 75 years of age who underwent R0 gastrectomy for gastric cancer and who were diagnosed with T1 disease at National Cancer Center Hospital between 2005 and 2012. Long-term postoperative pneumonia was diagnosed by chest computed tomography every year until 2 years after surgery. The presence of preoperative sarcopenia was assessed using preoperative L3 skeletal muscle index.

Results

167 patients were included in this study. Long-term postoperative pneumonia was observed in 44 (26%) patients. Of the 44 people diagnosed with long-term postoperative pneumonia, 33 were diagnosed in the 1st year and 11 in the 2nd year. 117 patients (70%) were diagnosed with sarcopenia which was significantly frequently found in the patients who developed long-term postoperative pneumonia (91%) than those without (63%). Preoperative sarcopenia was the only independent risk factor in multivariate analysis. Type of gastrectomy was not a significant risk factor.

Conclusions

Long-term postoperative pneumonia was frequently observed in the elderly patients. Preoperative sarcopenia was associated with long-term postoperative pneumonia in elderly patients who underwent curative surgery for gastric cancer. After gastrectomy, long-term special care would be required for elderly patients, especially with sarcopenia.
The evaluation of muscle strength and architecture in type 1 diabetes mellitus: a cross-sectional study
Authors: Tan Sefa , Gunendi Zafer , Meray Jale , Yetkin İlhan
Published: June 2022

Background

The aim of this study is to compare muscle strength and architecture between type 1 diabetes patients and healthy volunteers and to assess whether there is an ultrasonographic structural change in this population.

Methods

Thirty-two patients with T1D (23 female, 9 male) with an age average of 31.3 ± 8.7 years, matched in terms of age, gender, height, weight and physical activity were included in the study. In the T1D and control group, ultrasonographic measurements of quadriceps femoris muscle (RF, VI, VM, VL) and pennate angle (VI, VM, VL) were performed. Muscle strength values were measured using isokinetic dynamometer system at angular velocities of 60º/s and 180º/s in both groups.

Results

Initially, both groups were similar in demographic and clinical characteristics (p > 0.05). In the T1D group, there was a statistically significant difference in flexion/extension peak torque measurements at an angular velocity of 60º/s compared to the control group (p < 0.05). In support of these isokinetic measurements, RF, VI, VM, VL muscle thicknesses and VI, VM pennate angle measurements in T1Ds were significantly lower (p < 0.05). When the T1D group was subgrouped according to HbA1C and diabetes duration, there was no significant difference in ultrasonographic and isokinetic measurements between the two groups (p > 0.05). When the T1D group was subgrouped, in the group that used insulin pump RF, VI, VM muscle thickness measurements were significantly higher (p < 0.05) than the group using subcutaneous insulin.

Conclusions

This study supports that muscle strength and architecture are adversely affected in the T1D patient group, insulin deficiency is a risk factor for sarcopenia and this can be shown through ultrasonography. It can also be said that insulin pump use has more positive effects in terms of diabetic myopathy than subcutaneous insulin, and diabetic myopathy develops independently of other diabetic complications. As a result, the muscle architecture of T1D people is adversely affected by insulin deprivation, so regular physical activity should be an integral part of diabetes treatment.
Effect of enamel-surface modifications on shear bond strength using different adhesive materials
Authors: Zheng Bo-wen , Cao Shan , Al-Somairi Majedh Abdo Ali , He Jia , Liu Yi
Published: June 2022

Background

This study aimed to investigate the effect of enamel-surface modifications on the shear bond strength between ceramic brackets bonded using different adhesive materials and the enamel surface and to identify the most suitable clinical adhesive and bonding method. Whether the non-acid-etching treatment met the clinical bond strength was also determined.

Methods

A total of 108 extracted premolars were divided into nine groups (n = 12) based on the different enamel-surface modification techniques (acid etching, deproteinization, and wetting). Group 1 was bonded with Transbond™ XT adhesive, whereas groups 2–9 were bonded with resin-modified glass ionomer cement (RMGIC). The treatment methods for each group were as follows: groups 1 and 2, acid etching; group 3, acid etching and wetting; group 4, acid etching and deproteinization; group 5, acid etching, deproteinization, and wetting; group 6, deproteinization; group 7, deproteinization and wetting; group 8, without treatment; and group 9, wetting. The samples' shear bond strength was measured using an universal testing machine. Adhesive remnant index (ARI) was examined using a stereomicroscope. The enamel-surface morphology was observed with a scanning electron microscope. One-way ANOVA with Tukey’s post-hoc test and chi-square test were used for statistical analysis, and p < 0.05 and α = 0.05 were considered statistically significant.

Results

The ARIs of groups 1–5 and 6–9 were statistically significant (p = 0.000). The enamel surface of groups 1–5 was demineralized, and only a tiny amount of protein remained in groups 7 and 8, whereas a thick layer of protein remained in groups 8 and 9.

Conclusions

RMGIC adhesive did not damage the enamel surface and achieved the required clinical bond strength. The enamel surface was better treated with 5.25% sodium hypochlorite preferably under non-acid-etching conditions.
Exploring the mechanism and experimental verification of puerarin in the treatment of endometrial carcinoma based on network pharmacology and bioinformatics analysis
Authors: Lin Zhiheng , Sui Xiaohui , Jiao Wenjian , Wang Ying , Zhao Junde
Published: June 2022

Endometrial carcinoma is one of the two cancers with rising mortality and morbidity in recent years. In the light of many controversies about its treatment, it is urgent to construct a new prognostic model and to find out new therapeutic directions. As a small drug molecule widely used in clinical treatment and experimental research in China, puerarin has recently been proven to have obvious anti-cancer effects in multiple cancer cells. In this study, bioinformatics analysis and experimental validation were used to explore the potential mechanism of puerarin for endometrial carcinoma and construct a prognostic model. A total of 22 drug-related differential genes were found by constructing a database of drug targets and disease genes. The protein–protein interaction network was constructed for GO and KEGG enrichment analysis to initially explore the potential mechanism of its therapeutic effects. To construct the prognostic model, validation was performed by risk regression analysis and LASSO analysis. Finally, two prognostic genes—PIM1 and BIRC5 were determined to establish high and low risk groups. Kaplan–Meier analysis displayed a higher survival rate in the low-risk group than in the high-risk group. ROC curves indicated the stable and good effect in prediction (one-year AUC is 0.626; two-year AUC is 0.620; three-year AUC is 0.623). The interrelationship between immunity and its disease was explored by immune infiltration analysis. Finally, the potential effect of puerarin on endometrial carcinoma cells was further verified by experiments.
Public attitudes towards sharing loyalty card data for academic health research: a qualitative study
Authors: Dolan Elizabeth H. , Shiells Kate , Goulding James , Skatova Anya
Published: June 2022

Background

A growing number of studies show the potential of loyalty card data for use in health research. However, research into public perceptions of using this data is limited. This study aimed to investigate public attitudes towards donating loyalty card data for academic health research, and the safeguards the public would want to see implemented. The way in which participant attitudes varied according to whether loyalty card data would be used for either cancer or COVID-19 research was also examined.

Methods

Participants (N = 40) were recruited via Prolific Academic to take part in semi-structured telephone interviews, with questions focused on data sharing related to either COVID-19 or ovarian/bowel cancer as the proposed health condition to be researched. Content analysis was used to identify sub-themes corresponding to the two a priori themes, attitudes and safeguards.

Results

Participant attitudes were found to fall into two categories, either rational or emotional. Under rational, most participants were in favour of sharing loyalty card data. Support of health research was seen as an important reason to donate such data, with loyalty card logs being considered as already within the public domain. With increased understanding of research purpose, participants expressed higher willingness to donate data. Within the emotional category, participants shared fears about revealing location information and of third parties obtaining their data. With regards to safeguards, participants described the importance of anonymisation and the level of data detail; the control, convenience and choice they desired in sharing data; and the need for transparency and data security. The change in hypothetical purpose of the data sharing, from Covid-19 to cancer research, had no impact on participants’ decision to donate, although did affect their understanding of how loyalty card data could be used.

Conclusions

Based on interviews with the public, this study contributes recommendations for those researchers and the wider policy community seeking to obtain loyalty card data for health research. Whilst participants were largely in favour of donating loyalty card data for academic health research, information, choice and appropriate safeguards are all exposed as prerequisites upon which decisions are made.
Screening is not always healthy: an ethical analysis of health screening packages in Singapore
Authors: Yong Sarah Ee Fang , Wong Mee Lian , Voo Teck Chuan
Published: June 2022

Background

Health screening is undertaken to identify individuals who are deemed at higher risk of disease for further diagnostic testing so that they may possibly benefit from interventions to modify the natural course of disease. In Singapore, screening tests are widely available in the form of a package, which bundles multiple tests in one session and commonly includes non-recommended tests. There are various ethical issues associated with such testing as they may not be clinically appropriate and can result in more harm than benefit. This article describes the practice of health screening packages, identifies the ethical issues arising from such packages and discusses the implications of these ethical issues on policy and practice of screening in Singapore.

Methods

A content analysis of the websites of providers offering general health screening packages to individuals was conducted. A total of 14 health screening package providers were analysed for how packages were conducted and promoted, how clinically appropriate screening tests were, and the price range and composition of screening packages. A normative ethical analysis based on the four principles approach of beneficence, non-maleficence, autonomy and justice in biomedical ethics was used.

Results

Twelve of the 14 providers included non-recommended tests such as tumour markers, treadmill stress tests and MRI scans in their general health screening packages. Package prices ranged from S$26 to S$10,561, with providers charging higher when more tests were included. Health screening packages were broadly conducted in three stages: (1) the offer and selection of a health screening package; (2) medical assessment and performance of screening tests; (3) a post-screening review. While material provided by all providers was factual, there was no information on the potential risks or harms of screening.

Conclusion

Several ethical issues were identified that should be addressed with regard to health screening packages in Singapore. A key issue was the information gap between providers and patients, which may result in patients undergoing inappropriate testing that may be more harmful than beneficial. Health screening packages can stimulate unnecessary demand for healthcare and contribute to an inequitable distribution of healthcare resources.
Digital quantification of p16-positive foci in fibrotic interstitial lung disease is associated with a phenotype of idiopathic pulmonary fibrosis with reduced survival
Authors: Keow Jonathan , Cecchini Matthew J. , Jayawardena Nathashi , Zompatori Maurizio , Joseph Mariamma G. , Mura Marco
Published: June 2022

Background

Idiopathic pulmonary fibrosis (IPF) is associated with increased expression of cyclin-dependent kinase inhibitors such as p16 and p21, and subsequent induction of cell cycle arrest, cellular senescence, and pro-fibrotic gene expression. We sought to link p16-expression with a diagnosis of IPF or other fibrotic interstitial lung diseases (ILDs), radiographic pattern, senescent foci-specific gene expression, antifibrotic therapy response, and lung transplant (LTx)-free survival.

Methods

Eighty-six cases of fibrosing ILD were identified with surgical lung biopsy. Immunohistochemistry for p16 was performed on sections with the most active fibrosis. p16-positive foci (loose collection of p16-positive fibroblasts with overlying p16-positive epithelium) were identified on digital slides and quantified. Cases were scored as p16-low (≤ 2.1 foci per 100 mm2) or p16-high (> 2.1 foci per 100 mm2). Twenty-four areas including senescent foci, fibrotic and normal areas were characterized using in situ RNA expression analysis with digital spatial profiling (DSP) in selected cases.

Results

The presence of p16-positive foci was specific for the diagnosis of IPF, where 50% of cases expressed any level of p16 and 26% were p16-high. There was no relationship between radiographic pattern and p16 expression. However, there was increased expression of cyclin-dependent kinase inhibitors, collagens and matrix remodeling genes within p16-positive foci, and cases with high p16 expression had shorter LTx-free survival. On the other hand, antifibrotic therapy was significantly protective. DSP demonstrated that fibroblastic foci exhibit transcriptional features clearly distinct from that of normal-looking and even fibrotic areas.

Conclusions

We demonstrated the potential clinical applicability of a standardized quantification of p16-positive fibroblastic foci. This method identifies an IPF phenotype associated with foci-specific upregulation of senescence-associated and matrix remodeling gene expression. While these patients have reduced LTx-free survival, good response to antifibrotic therapies was observed in those who were treated.
Systems biology of malaria explored with nonhuman primates
Authors: Galinski Mary R.
Published: June 2022

“The Primate Malarias” book has been a uniquely important resource for multiple generations of scientists, since its debut in 1971, and remains pertinent to the present day. Indeed, nonhuman primates (NHPs) have been instrumental for major breakthroughs in basic and pre-clinical research on malaria for over 50 years. Research involving NHPs have provided critical insights and data that have been essential for malaria research on many parasite species, drugs, vaccines, pathogenesis, and transmission, leading to improved clinical care and advancing research goals for malaria control, elimination, and eradication. Whilst most malaria scientists over the decades have been studying Plasmodium falciparum, with NHP infections, in clinical studies with humans, or using in vitro culture or rodent model systems, others have been dedicated to advancing research on Plasmodium vivax, as well as on phylogenetically related simian species, including Plasmodium cynomolgi, Plasmodium coatneyi, and Plasmodium knowlesi. In-depth study of these four phylogenetically related species over the years has spawned the design of NHP longitudinal infection strategies for gathering information about ongoing infections, which can be related to human infections. These Plasmodium-NHP infection model systems are reviewed here, with emphasis on modern systems biological approaches to studying longitudinal infections, pathogenesis, immunity, and vaccines. Recent discoveries capitalizing on NHP longitudinal infections include an advanced understanding of chronic infections, relapses, anaemia, and immune memory. With quickly emerging new technological advances, more in-depth research and mechanistic discoveries can be anticipated on these and additional critical topics, including hypnozoite biology, antigenic variation, gametocyte transmission, bone marrow dysfunction, and loss of uninfected RBCs. New strategies and insights published by the Malaria Host–Pathogen Interaction Center (MaHPIC) are recapped here along with a vision that stresses the importance of educating future experts well trained in utilizing NHP infection model systems for the pursuit of innovative, effective interventions against malaria.
Do changes in primary care service use over time differ by neighbourhood income? Population-based longitudinal study in British Columbia, Canada
Authors: Lavergne M.R. , Bodner A. , Peterson S. , Wiedmeyer M. , Rudoler D. , Spencer S. , Marshall E.G.
Published: June 2022

Background

Strong primary care systems have been associated with improved health equity. Primary care system reforms in Canada may have had equity implications, but these have not been evaluated. We sought to determine if changes in primary care service use between 1999/2000 and 2017/2018 differ by neighbourhood income in British Columbia.

Methods

We used linked administrative databases to track annual primary care visits, continuity of care, emergency department (ED) visits, specialist referrals, and prescriptions dispensed over time. We use generalized estimating equations to examine differences in the magnitude of change by neighbourhood income quintile, adjusting for age, sex/gender, and comorbidity, and stratified by urban/rural location of residence. We also compared the characteristics of physicians providing care to people living in low- and high-income neighbourhoods at two points in time.

Results

Between 1999/2000 and 2017/8 the average number of primary care visits per person, specialist referrals, and continuity of care fell in both urban and rural settings, while ED visits and prescriptions dispensed increased. Over this period in urban settings, primary care visits, continuity, and specialist referrals fell more rapidly in low vs. high income neighbourhoods (relative change in primary care visits: Incidence Rate Ratio (IRR) 0.881, 95% CI: 0.872, 0.890; continuity: partial regression coefficient -0.92, 95% CI: -1.18, -0.66; specialist referrals: IRR 0.711, 95%CI: 0.696, 0.726), while ED visits increased more rapidly (IRR 1.06, 95% CI: 1.03, 1.09). The percentage of physicians who provide the majority of visits to patients in neighbourhoods in the lower two income quintiles declined from 30.6% to 26.3%.

Conclusion

Results raise concerns that equity in access to primary care has deteriorated in BC. Reforms to primary care that fail to attend to the multidimensional needs of low-income communities may entrench existing inequities. Policies that tailor patterns of funding and allocation of resources in accordance with population needs, and that align accountability measures with equity objectives are needed as part of further reform efforts.
Nanomaterials alleviating redox stress in neurological diseases: mechanisms and applications
Authors: Jiang Yanping , Kang Yiyuan , Liu Jia , Yin Suhan , Huang Zhendong , Shao Longquan
Published: June 2022

Overproduced reactive oxygen and reactive nitrogen species (RONS) in the brain are involved in the pathogenesis of several neurological diseases, such as Alzheimer's disease, Parkinson's disease, traumatic brain injury, and stroke, as they attack neurons and glial cells, triggering cellular redox stress. Neutralizing RONS, and, thus, alleviating redox stress, can slow down or stop the progression of neurological diseases. Currently, an increasing number of studies are applying nanomaterials (NMs) with anti-redox activity and exploring the potential mechanisms involved in redox stress-related neurological diseases. In this review, we summarize the anti-redox mechanisms of NMs, including mimicking natural oxidoreductase activity and inhibiting RONS generation at the source. In addition, we propose several strategies to enhance the anti-redox ability of NMs and highlight the challenges that need to be resolved in their application. In-depth knowledge of the mechanisms and potential application of NMs in alleviating redox stress will help in the exploration of the therapeutic potential of anti-redox stress NMs in neurological diseases.

Graphical Abstract
MXenes-integrated microneedle combined with asiaticoside to penetrate the cuticle for treatment of diabetic foot ulcer
Authors: Wang Pei , Wang Yun , Yi Yang , Gong Yan , Ji Haoran , Gan Yuci , Xie Fei , Fan Jinchen , Wang Xiansong
Published: June 2022

Patients with diabetic foot ulcers usually suffer from inefficient epithelisation and angiogenesis accompanied by chronic wound healing. Diabetic foot ulcers remain a major challenge in clinical medicine; however, traditional treatments are incapable of transdermal drug delivery, resulting in a low drug delivery rate. We report the development of Ti2C3 MXenes-integrated poly-γ-glutamic acid (γ-PGA) hydrogel microneedles to release asiaticoside (MN-MXenes-AS). Asiaticoside was loaded into PGA-MXenes hydrogel to facilitate cell proliferation while regulating angiogenesis. The characterisation and mechanical strength of the microneedles were investigated in vitro, and the wound-healing efficacy of the microneedles was confirmed in diabetic mice. MXenes significantly improved the mechanical strength of microneedles, while γ-PGA hydrogels provided a moist microenvironment for wound healing. Mice treated with MN-MXenes-AS demonstrated obvious improvements in wound healing process. We successfully fabricated an MXenes-integrated microneedle that possesses sufficient rigidity to penetrate the cuticle for subcutaneous drug delivery, thereby accelerating diabetic wound healing. We demonstrated that MN-MXenes-AS is effective in promoting growth both in vivo and in vitro. Collectively, our data show that MN-MXenes-AS accelerated the healing of diabetic foot ulcers, supporting the use of these microneedles in the treatment of chronic wounds.

Graphical Abstract
Dual-binding nanoparticles improve the killing effect of T cells on solid tumor
Authors: Luo Zhenyu , Luo Lihua , Lu Yichao , Zhu Chunqi , Qin Bing , Jiang Mengshi , Li Xiang , Shi Yingying , Zhang Junlei , Liu Yu , Shan Xinyu , Yin Hang , Guan Guannan , Du Yongzhong , Cheng Ningtao , You Jian
Published: June 2022

Adoptive cell therapy (ACT) was one of the most promising anti-tumor modalities that has been confirmed to be especially effective in treating hematological malignancies. However, the clinical efficacy of ACT on solid tumor was greatly hindered by the insufficient tumor-infiltration of cytotoxic CD8 + T cells. Herein, we constructed a nanoplatform termed dual-binding magnetic nanoparticles (DBMN) that comprised PEG-maleimide (Mal), hyaluronic acid (HA) and Fe3O4 for adoptive T cell-modification and ACT-sensitization. After a simple co-incubation, DBMN was anchored onto the cell membrane (Primary linking) via Michael addition reaction between the Mal and the sulfhydryl groups on the surface of T cells, generating magnetized T cells (DBMN-T). Directed by external magnetic field and in-structure Fe3O4, DBMN-T was recruited to solid tumor where HA bond with the highly expressed CD44 on tumor cells (Secondary Linking), facilitating the recognition and effector-killing of tumor cells. Bridging adoptive T cells with host tumor cells, our DBMN effectively boosted the anti-solid tumor efficacy of ACT in a mouse model and simultaneously reduced toxic side effects.
Junctional adhesion molecule-like protein promotes tumor progression via the Wnt/β-catenin signaling pathway in lung adenocarcinoma
Authors: Wu Qian , Li Rui , Wang Qing-Xiang , Zhang Meng-Yu , Liu Ting-Ting , Qu Yi-Qing
Published: June 2022

Background

Lung adenocarcinoma (LUAD) is a heavy social burden worldwide. Because the mechanisms involved in LUAD remain unclear, the prognosis of LUAD remains poor. Consequently, it is urgent to investigate the potential mechanisms of LUAD. Junctional adhesion molecule-like protein (JAML), is recognized as a tumorigenesis molecule in gastric cancer. However, the role of JAML in LUAD is still unclear. Here we aimed to evaluate the role of JAML in LUAD.

Methods

qRT-PCR, Western blotting and immunohistochemistry were conducted to investigate the expression of JAML in LUAD tissues. JAML was knocked down and overexpressed in LUAD cells using transient transfection by siRNA and plasmids or stable transfection by lentivirus. Proliferation potential of LUAD cells were detected by Cell Counting Kit-8, EdU incorporation and Colony formation assay. Migration and invasion abilities of LUAD cells were determined by wound healing, transwell migration and invasion assays. Cell cycle and cell apoptosis were detected by flow cytometry. The effects of JAML in vivo were studied in xenograft tumor models. Western blotting was used to explore the molecular mechanisms of JAML function. In addition, rescue experiments were performed to verify the possible mechanisms.

Results

JAML expression was elevated in LUAD tissues compared with peritumor tissues, and this upregulation was positively related to pT and pTNM. Furthermore, both in vitro and in vivo, JAML silencing markedly repressed malignant behaviors of LUAD cells and vice versa. Knockdown of JAML also mediated cell cycle arrest at G0/G1 phase and promoted apoptosis in LUAD cells. Mechanistically, silencing JAML repressed the process of epithelial-mesenchymal transition by inactivating the Wnt/β-catenin pathway in LUAD cells. Effects of JAML can be rescued by Wnt/β-catenin pathway activator in A549 cells.

Conclusions

Our data reveal the oncogenic role of JAML in LUAD, indicating that JAML may be a predictive biomarker and novel therapeutic target for LUAD.
Dengue infection triggered immune mediated necrotizing myopathy in children: a case report and literature review
Authors: Mekmangkonthong Aphirak , Amornvit Jakkrit , Numkarunarunrote Numphung , Veeravigrom Montida , Khaosut Parichat
Published: June 2022

Background

Immune-mediated necrotizing myopathy (IMNM) is a subgroup of idiopathic inflammatory myopathies manifesting with progressive weakness, elevated serum creatine kinase (CK) levels, and necrotizing myopathic features on muscle biopsy. There is a paucity of data on the clinical presentation of IMNM in children. We report a paediatric patient who developed anti-3-hydroxy-3-methylglutaryl-CoA reductase (anti-HMGCR)-positive necrotizing myopathy after recent dengue infection.

Case presentation

A previously healthy 9-year-old boy presented with acute proximal muscle weakness after recovery from dengue infection. Five days after the fever subsided, he could not stand from a squatting position. He denied having skin rash, arthritis, or other systemic features. He had marked elevation of CK level of 30,833 mg/dL and was put on steroid therapy. The patient initially responded to oral prednisolone, however the weakness persisted and muscle enzymes increased as steroids were decreased. He was then referred to our hospital for further assessment. Subsequent investigation revealed anti-HMGCR positivity along with specific histopathological findings consistent with IMNM. The patient was treated with six cycles of intravenous immunoglobulin (IVIG) monthly, then followed by a gradual taper of prednisolone and oral methotrexate weekly with complete recovery in motor power.

Conclusions

Our report presents a child with clinical manifestations of IMNM which can be categorized as acute onset of muscle weakness following dengue infection. Two key points supporting a diagnosis in this case are clinical response after immunosuppressive therapy and absence of rashes found in juvenile dermatomyositis.
Vascular network expansion, integrity of blood–brain interfaces, and cerebrospinal fluid cytokine concentration during postnatal development in the normal and jaundiced rat
Authors: Blondel Sandrine , Strazielle Nathalie , Amara Amel , Guy Rainui , Bain Christine , Rose Alix , Guibaud Laurent , Tiribelli Claudio , Gazzin Silvia , Ghersi-Egea Jean-François
Published: June 2022

Background

Severe neonatal jaundice resulting from elevated levels of unconjugated bilirubin in the blood induces dramatic neurological impairment. Central oxidative stress and an inflammatory response have been associated with the pathophysiological mechanism. Cells forming the blood–brain barrier and the choroidal blood–CSF barrier are the first CNS cells exposed to increased plasma levels of unconjugated bilirubin. These barriers are key regulators of brain homeostasis and require active oxidative metabolism to fulfill their protective functions. The choroid plexus-CSF system is involved in neuroinflammatory processes. In this paper, we address the impact of neonatal hyperbilirubinemia on some aspects of brain barriers. We describe physiological changes in the neurovascular network, blood–brain/CSF barriers integrities, and CSF cytokine levels during the postnatal period in normobilirubinemic animals, and analyze these parameters in parallel in Gunn rats that are deficient in bilirubin catabolism and develop postnatal hyperbilirubinemia.

Methods

Gunn rats bearing a mutation in UGT1a genes were used. The neurovascular network was analyzed by immunofluorescence stereomicroscopy. The integrity of the barriers was evaluated by [14C]-sucrose permeability measurement. CSF cytokine levels were measured by multiplex immunoassay. The choroid plexus-CSF system response to an inflammatory challenge was assessed by enumerating CSF leukocytes.

Results

In normobilirubinemic animals, the neurovascular network expands postnatally and displays stage-specific regional variations in its complexity. Network expansion is not affected by hyperbilirubinemia. Permeability of the blood–brain and blood–CSF barriers to sucrose decreases between one- and 9-day-old animals, and does not differ between normobilirubinemic and hyperbilirubinemic rats. Cytokine profiles differ between CSF and plasma in all 1-, 9-, and 18-day-old animals. The CSF cytokine profile in 1-day-old animals is markedly different from that established in older animals. Hyperbilirubinemia perturbs these cytokine profiles only to a very limited extent, and reduces CSF immune cell infiltration triggered by systemic exposure to a bacterial lipopeptide.

Conclusion

The data highlight developmental specificities of the blood–brain barrier organization and of CSF cytokine content. They also indicate that a direct effect of bilirubin on the vascular system organization, brain barriers morphological integrity, and inflammatory response of the choroid plexus-CSF system is not involved in the alteration of brain functions induced by severe neonatal jaundice.
Monteggia fractures: analysis of patient-reported outcome measurements in correlation with ulnar fracture localization
Authors: Tille Eric , Seidel L. , Schlüßler A. , Beyer Franziska , Kasten P. , Bota O. , Biewener A. , Nowotny J.
Published: June 2022

Background

Monteggia fractures and Monteggia-like lesions result after severe trauma and have high complication rates. Preliminary biomechanical studies suggested a correlation between ulnar fracture localization and clinical result.

Objectives

Key objective was to evaluate whether the site of the ulnar fracture can be correlated to clinical outcome after open reduction and internal stabilization.

Methods

In a retrospective, monocentric study 35 patients who underwent surgical treatment after suffering a Monteggia injury or Monteggia-like lesion were included. Fractures were classified according to Bado and Jupiter, the site of the fracture location at the proximal ulna and regarding the potential accompanying ligamentary injury. In a follow-up examination validated patient-reported outcome measures and functional parameters were evaluated. Furthermore, treatment strategy and complications were analysed.

Results

Mean patient age was 51.9 years (± 18.0). 69% were females (n = 24). Follow-up took place after 50.5 months (± 22.1). Fractures were classified according to Bado (I:2, II:27, III:4, IV:2). Bado II-fractures were further classified according to Jupiter (A:7, B:16, C:3, D:1). Cases were divided into subgroups depending upon the distance of the ulnar fracture site in respect to its distal endpoint (A: < 7 cm and B: > 7 cm). Average overall MEPS was 84.1 (± 19.0). Oxford elbow score and DASH were 37.2 (± 10.5) and 20.4 (± 20.5). Average extension capability reached − 7° (± 7.5). Mean flexion was 134.8° (± 19.7). Average pain according to visual analogue scale was 1.6 (± 1.9). We found no differences between the subgroups regarding the PROMs. Subgroup A displayed a worse extension capability (p = 0.027) and patients were significantly older (p < 0.01). Comparing patients with and without fracture of the radial head, we observed no differences. Patients with an accompanying injury of the coronoid process displayed higher pain levels (p = 0.011), a worse functionality (p = 0.027) and overall lower scoring in PROM.

Conclusion

The presented results suggest that in Monteggia fractures and Monteggia-like lesions, the localization of the ulna fracture can give a hint for its postoperative outcome. However, we could not confirm the hypothesis of an increasing instability in ulnar fractures located further distally (high severity of the potential ligamentous injury). Intraarticular fractures or injuries with a close relation to the joint have a worse prognosis, especially if the coronoid process is injured.

Trial registration Registration was done with ClinicalTrials.gov under NCT05325268.
Concurrent double aortic arch and circumflex aorta repair in a symptomatic child: a case report
Authors: Hurtado Christopher G. , Nelson Jennifer S.
Published: June 2022

Double aortic arch with circumflex aorta is a rare type of vascular ring. Symptoms result from external compression of the trachea and esophagus. The best surgical approach for patients with double arch and circumflex aorta is debated, and options include the highly complex aortic uncrossing procedure. Herein we describe the surgical treatment of a patient with concurrent double aortic arch and circumflex aorta by division of the non-dominant arch and ligamentum arteriosum, plication and posterior tacking of the diverticulum of Kommerell. This left thoracotomy approach provided complete symptom resolution.