bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations of keratinocyte cancers with snp variants in the sonic hedgehog pathway
Authors: Rodriguez-Acevedo Astrid J. , Antonsson Annika , Liyanage Upekha E. , Hughes Maria Celia , Gordon Scott , van der Pols Jolieke , Green Adele C.
Published: May 2022

Background

Sonic Hedgehog (SHH) pathway dysregulation is implicated in basal cell carcinoma (BCC) development. To evaluate the possible wider role of SHH gene variants in skin carcinogenesis, we assessed associations of genes in the SHH pathway with lifetime development of any keratinocyte cancer (KC), and with developing either BCCs or squamous cell carcinomas (SCCs) exclusively, in a 25-year prospective, population-based study of 1,621 Australians.

Methods

We genotyped 795 unrelated adults with available blood samples: 311 cases with any KC (186 developing BCCs-only, 55 SCCs-only, 70 BCCs and SCCs) and 484 controls. We compared allele frequencies of 158 independent SNPs across 43 SHH genes between cases and controls, and performed a gene-based analysis.

Results

We found associations between SNP rs4848627 (GLI2) (related to DNA synthesis in keratinocytes) and development of any KC (OR = 1.53; 95% CI = 1.06–2.13, P < 0.01) and SCCs exclusively (OR = 2.12; 95%CI = 1.39–3.23, P < 0.01). SNP rs3217882 located in CCND2 was associated with exclusive BCC development (OR = 1.43, CI = 1.12–1.82, P < 0.01). The gene-based analysis suggested an association of PRKACG (protein kinase cAMP-activated catalytic subunit gamma) with any KC (P = 0.013).

Conclusion

We conclude that variants located in genes in the SHH pathway may are involved in SCC as well as BCC development.
Thoracic kyphosis in light of lumbosacral alignment in thoracic adolescent idiopathic scoliosis: recognition of thoracic hypokyphosis and therapeutic implications
Authors: Iimura Takuya , Ueda Haruki , Inami Satoshi , Moridaira Hiroshi , Takeuchi Daisaku , Aoki Hiromichi , Taneichi Hiroshi
Published: May 2022

Background

The uniqueness of spinal sagittal alignment in thoracic adolescent idiopathic scoliosis (AIS), for example, the drastically smaller thoracic kyphosis seen in some patients, has been recognized but not yet fully understood. The purpose of this study was to clarify the characteristics of sagittal alignment of thoracic AIS and to determine the contributing factors.

Methods

Whole spine radiographs of 83 thoracic AIS patients (73 females) were analyzed. The measured radiographic parameters were the Cobb angle of thoracic scoliosis, thoracic kyphosis (TK), lumbar lordosis (LL), C7 sagittal vertical axis (C7 SVA), pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS). Additionally, max-LL, which was defined as the maximum lordosis angle from the S1 endplate, the inflection point between thoracic kyphosis and lumbar lordosis, and the SVA of the inflection point (IP SVA) were measured. The factors significantly related to a decrease in TK were assessed by stepwise logistic regression analysis. In addition, cluster analysis was performed to classify the global sagittal alignment.

Results

The significant factors for a decrease in TK were an increase in SS (p = 0.0003, [OR]: 1.16) and a decrease in max-LL (p = 0.0005, [OR]: 0.89). According to the cluster analysis, the global sagittal alignment was categorized into the following three types: Type 1 (low SS, low max-LL, n = 28); Type 2 (high SS, low max-LL, n = 22); and Type 3 (high SS, high max-LL, n = 33).

Conclusions

In thoracic AIS, a decreased TK corresponded to an increased SS or a decreased max-LL. The sagittal alignment of thoracic AIS patients could be classified into three types based on SS and max-LL. One of these three types includes the unique sagittal profile of very small TK.
Student characteristics associated with interpersonal skills in medical consultations
Authors: Bellier Alexandre , Chaffanjon Philippe , Morand Patrice , Palombi Olivier , Francois Patrice , Labarère José
Published: May 2022

Background

The quality of medical care depends on effective physician–patient communication. Interpersonal skills can be improved through teaching, but the determinants are poorly understood. We therefore assessed the factors associated with the interpersonal skills of medical students during simulated medical consultations.

Methods

We conducted a cross-sectional study of fourth-year medical students participating in simulated consultations with standardized patients. Each video-recorded medical consultation was independently assessed by two raters, using a cross-cultural adaptation of the Four Habits Coding Scheme (4-HCS) into French. We then collected information on demographics and education-related characteristics. The relationship between the overall 4-HCS score and student characteristics was modeled using univariable and multivariable linear regression.

Results

Our analytical sample included 165 medical students for analysis. The factors significantly associated with 4-HCS score were gender (β = − 4.8, p = 0.011) and completion of an international clinical placement (β = 6.2, p = 0.002) or a research laboratory clerkship (β = 6.5, p = 0.005). Education-related characteristics, multiple-choice examinations in the first to third preclinical years, and number of medicine or surgery clerkships were not significantly associated with 4-HCS score.

Conclusions

Undergraduate students with higher level of interpersonal skills during video-recorded medical consultations with standardized patients are more likely to be female, to have completed international clinical placement as part of the ERASMUS exchange program or research laboratory clerkship.
Experiences of simulated patients in providing feedback in communication skills teaching for undergraduate medical students
Authors: George Riya Elizabeth , Wells Harvey , Cushing Annie
Published: May 2022

Background

Simulated Patients (SPs) are commonplace in the teaching of communication skills in medical education and can provide immediate feedback to students from the patient’s perspective. The experiences of SPs and their perspective on providing feedback is an under-studied area. This study aims to explore SP experiences and views on feedback, factors influencing their feedback and implications for training.

Methods

Using a constructivist grounded theory approach, we conducted six focus groups with 30 SPs. Participants included experienced simulated patients from a London-based actor agency, used in undergraduate teaching programmes of communication skills. Consistent with the principles of grounded theory, data was collected and analysed in an iterative process to identify themes.

Results

Five over-arching themes were identified: 1.) Feedback processes, 2.) Challenges in providing feedback, 3.) Cumulative experiences, 4.) Web of interpersonal relationships and dynamics and 5.) Portraying the character and patient representations.

Discussion

These SPs regarded the sharing of the emotions they experienced during the consultation as the focus of their feedback. Their preference was for giving a ‘sandwich style’ of feedback and ‘out-of-role’ approach. The relationship with facilitators and students and politeness conventions emerged as significant factors when providing feedback. Sensitivity to the social dynamics of groups and implicit facilitator expectations were challenges they experienced as was divergence in views of student performance.

Conclusion

This study explored SP experiences and perspectives on providing feedback. Findings reveal complex social and structural dynamics at play in providing feedback which have not been reported so far in the literature. It is recommended that these issues should be addressed in training of both SPs and facilitators, in addition to feedback guidelines.
Electronic health record implementation and healthcare workers’ work characteristics and autonomous motivation—a before-and-after study
Authors: Veenstra Gepke L. , Rietzschel Eric F. , Molleman Eric , Heineman Erik , Pols Jan , Welker Gera A.
Published: May 2022

Background

Technological innovation in healthcare is often assumed to contribute to the quality of care. However, the question how technology implementation impacts healthcare workers has received little empirical attention. This study investigates the consequences of Electronic Health Record (EHR) implementation for healthcare workers’ autonomous work motivation. These effects are further hypothesized to be mediated by changes in perceived work characteristics (job autonomy and interdependence). Additionally, a moderating effect of profession on the relationship between EHR implementation and work characteristics is explored.

Methods

A quantitative uncontrolled before-and-after study was performed among employees from a large university medical centre in the Netherlands. Data were analysed following the component approach for testing a first stage moderated mediation model, using Generalized Estimating Equations (GEE).

Results

A total of 456 healthcare workers (75 physicians, 154 nurses, 145 allied healthcare professionals, and 82 administrative workers) finished both the baseline and the follow-up survey. After EHR implementation, perceived job autonomy decreased, whereas interdependence increased. In line with our hypothesis, job autonomy was positively associated with autonomous motivation. In contrast to our expectations, interdependence also showed a positive association with autonomous motivation. Autonomous motivation was stable over the course of EHR implementation. This study did not provide support for a moderating effect of profession: no differences were observed between the various professions regarding the changes in their experienced job autonomy and interdependence after EHR implementation.

Conclusions

Our study showed that healthcare professionals’ perceptions of their work characteristics, but not their autonomous motivation, were changed after EHR implementation, and that these experiences were relatively similar for physicians, nurses, and allied healthcare professionals. The stability of healthcare workers’ autonomous motivation may be explained by the opposite effects of decreased job autonomy and increased interdependence, and by the EHR being in line with healthcare workers’ values. The changes in job autonomy and interdependence may have consequences beyond motivation, for example by affecting clinical decision-making, proactive behaviour, and the quality of teamwork. These potential consequences of EHR implementation warrant further research.
Electronic prescribing systems as tools to improve patient care: a learning health systems approach to increase guideline concordant prescribing for venous thromboembolism prevention
Authors: Gallier S. , Topham A. , Nightingale P. , Garrick M. , Woolhouse I. , Berry M. A. , Pankhurst T. , Sapey E. , Ball S.
Published: May 2022

Background

Venous thromboembolism (VTE) causes significant mortality and morbidity in hospitalised patients. Risk factors for VTE are well known and there are validated risk assessment tools to support the use of prophylactic therapies. In England, reporting the percentage of patients with a completed VTE risk assessment is mandated, but this does not include whether that risk assessment resulted in appropriate prescribing. Full guideline compliance, defined as an assessment which led to an appropriate action—here prescribing prophylactic low molecular weight heparin where indicated, is rarely reported. Education, audit and feedback enhance guideline compliance but electronic prescribing systems (EPS) can mandate guideline-compliant actions. We hypothesised that a systems-based EPS intervention (prescribing rules which mandate approval or rejection of a proposed prescription of prophylactic low molecular weight heparin based on the mandated VTE assessment) would increase full VTE guideline compliance more than interventions which focused on targeting individual prescribers.

Methods

All admitted patients within University Hospitals Birmingham NHS Foundation Trust were included for analysis between 2011 and 2020. The proportion of patients who received a fully compliant risk assessment and action was assessed over time. Interventions included teaching sessions and face-to-face feedback based on measured performance (an approach targeting individual prescribers) and mandatory risk assessment and prescribing rules into an EPS (a systems approach).

Results

Data from all 235,005 admissions and all 5503 prescribers were included in the analysis. Risk assessments were completed in > 90–95% of all patients at all times, but full guideline compliance was lower (70% at the start of this study). Face-to-face feedback improved full VTE guideline compliance from 70 to 77% (p ≤ 0.001). Changes to the EPS to mandate assessment with prescribing rules increased full VTE compliance to 95% (p ≤ 0.001). Further amendments to the EPS system to reduce erroneous VTE assessments slightly reduced full compliance to 92% (p < 0.001), but this was then maintained including during changes to the low molecular weight heparin used for VTE prophylaxis.

Discussion

An EPS-systems approach was more effective in improving sustained guideline-compliant VTE prevention over time. Non-compliance remained at 8–5% despite this mandated system. Further research is needed to assess the potential reasons for this.
An exploratory study of client and provider experience and perceptions of facility-based childbirth care in Quiché, Guatemala
Authors: Sethi Reena , Hill Kathleen , Stalls Suzanne , Moffson Susan , de Tejada Sandra Saenz , Gomez Leonel , Marroquin Miguel Angel
Published: May 2022

Introduction

Respectful maternity care (RMC) is fundamental to women’s and families’ experience of care and their decision about where to give birth. Studies from multiple countries describe the mistreatment of women during facility-based childbirth, though only a small number of studies from Guatemala have been published. Less information is available on women’s negative and positive experiences of childbirth care and health workers’ perceptions and experiences of providing maternity care.

Methods

As part of a program implemented in the Western Highlands of Guatemala to improve quality of reproductive maternal newborn and child health care, a mixed methods assessment was conducted in three hospitals and surrounding areas to understand women’s and health workers’ experience and perceptions of maternity care. The quantitative component included a survey of 31 maternity health workers and 140 women who had recently given birth in these hospitals. The qualitative component included in-depth interviews (IDIs) and focus group discussions (FGDs) with women and maternity health workers and managers.

Results

Women reported a mix of positive and negative experiences of childbirth care related to interpersonal and health system factors. 81% of surveyed women reported that health workers had treated them with respect while 21.4% of women reported verbal abuse. Fifty-five percent and 12% of women, respectively, reported not having access to a private toilet and bath or shower. During IDIs and FGDs, many women described higher rates of verbal abuse directed at women who do not speak Spanish. A regression analysis of survey results indicated that speaking Ixil or K’iche at home was associated with a higher likelihood of women being treated negatively during childbirth in a facility. Health worker survey results corroborated negative aspects of care described by women and also reported mistreatment of health workers by clients and families (70.9%) and colleagues (48.2%).

Conclusions

This study adds to the literature on women’s experience of institutional childbirth and factors that influence this experience by triangulating experience and perceptions of both women and health workers. This assessment highlights opportunities to address mistreatment of both women and health workers and to build on positive care attributes to strengthen RMC for all women.
Building integrated, adaptive and responsive healthcare systems – lessons from paramedicine in Ontario, Canada
Authors: Allana Amir , Kuluski Kerry , Tavares Walter , Pinto Andrew D.
Published: May 2022

Background

Being responsive and adaptive to local population needs is a key principle of integrated care, and traditional top-down approaches to health system governance are considered to be ineffective. There is need for more guidance on taking flexible, complexity-aware approaches to governance that foster integration and adaptability in the health system. Over the past two decades, paramedics in Ontario, Canada have been filling gaps in health and social services beyond their traditional mandate of emergency transport. Studying these grassroots, local programs can provide insight into how health systems can be more integrated, adaptive and responsive.

Methods

Semi-structured interviews were conducted with people involved in new, integrated models of paramedic care in Ontario. Audio recordings of interviews were transcribed and coded inductively for participants’ experiences, including drivers, enablers and barriers to implementation. Thematic analysis was done to ascertain key concepts from across the dataset.

Results

Twenty-six participants from across Ontario’s five administrative health regions participated in the study. Participants described a range of programs that included acute, urgent and preventative care driven by local relationship networks of paramedics, hospitals, primary care, social services and home care. Three themes were developed that represent participants’ experiences implementing these programs in the Ontario context. The first theme, adapting and being nimble in tension with system structures, related to distributed versus central control of programs, a desire to be nimble and skepticism towards prohibitive legal and regulatory systems. The second theme, evolving and flexible professional role identity, highlighted the value and challenges of a functionally flexible workforce and interest in new roles amongst the paramedic profession. The third theme, unpredictable influences on program implementation, identified events such as the COVID-19 pandemic and changing government priorities as accelerating, redirecting or inhibiting local program development.

Conclusions

The findings of this study add to the discourse on governing health systems towards being more integrated, adaptive and responsive to population needs. Governance strategies include: supporting networks of local organizational relationships; considering the role of a functionally flexible health workforce; promoting a shared vision and framework for collaboration; and enabling distributed, local control and experimentation.
Referral-based transition to subsequent rehabilitation at home after stroke: one-year outcomes and use of healthcare services
Authors: Lindblom Sebastian , Tistad Malin , Flink Maria , Laska Ann Charlotte , von Koch Lena , Ytterberg Charlotte
Published: May 2022

Background

There is a lack of knowledge about patients’ journeys across the stroke care continuum, especially regarding the transition from inpatient to outpatient care and rehabilitation. Therefore, the aim of the present study was to explore and describe patterns of healthcare use over a one-year period, health outcomes at 3 and 12 months for patients following a referral-based transition to subsequent rehabilitation in the home, and the caregiver burden on their significant others. A further aim was to explore factors associated with the use of rehabilitation and healthcare after the referral-based transition to continued rehabilitation in the home for people recovering from a stroke.

Methods

Data regarding healthcare use during the first 12 months post-stroke was collected from the Region Stockholm computerized register. Data on patient characteristics, disease-related data, and functioning were retrieved drawn from medical records and questionnaires. Descriptive statistics were used to present healthcare use, participants’ characteristics, disease-related data, and patient functioning. Multivariable regression models were created to explore associations between the total number of outpatient contacts, total visits with the neurorehabilitation team, and the independent variables.

Results

The mean age for the 190 participants was 73 years for men and 78 years for women. Twenty-one participants (11%) had an acute rehospitalization within 30 days after discharge, and 41 participants (21%) were re-hospitalized within 90 days. Twenty-two (12%) of the participants had no visits with the neurorehabilitation team, 73 (39%) participants had 1–3 visits, 57 (30%) had 4–16 visits, and 38 (20%) had ≥17 visits. Female sex and length of hospital stay were associated with a higher number of visits with the neurorehabilitation team. Living alone, higher self-rated recovery, and being able to walk independently were associated with a lower number of visits with the neurorehabilitation team. Female sex, having home help services before the stroke, longer length of hospital stay, and more comorbidities were associated with a higher number of outpatient contacts.

Conclusions

The findings indicate that there is no generic pattern of healthcare use during the first-year post-stroke in patients receiving referral-based transition to continued rehabilitation in the home. The different patterns of healthcare use seemed to mirror the participants’ level of functioning. However, there is a need to further investigate how follow-up and rehabilitation correspond to the needs of patients and their significant others in the short- and long-term perspective.

Trial registration

ClinicalTrials.gov, registration number:NCT02925871. Date of registration: October 6, 2016.
Increasing person-centeredness in psychosis inpatient care: staff experiences from the Person-Centered Psychosis Care (PCPC) project
Authors: Allerby K. , Goulding A. , Ali L. , Waern M.
Published: May 2022

Background

Interventions to increase person-centeredness in hospital care for persons with psychotic illness are needed. Changing care delivery is however a complex venture, requiring staff to reconsider their mindsets and ways of working. A multidisciplinary educational intervention for hospital staff at four wards was launched to increase person-centeredness in the care of patients with schizophrenia and similar psychoses. This study aims to explore staff experiences of working to increase person-centeredness.

Methods

A heterogenic sample of staff (n = 23) from all participating wards were recruited for six focus group interviews. Semi-structured questions covered staff perceptions of person-centered care and the process of increasing person-centeredness. Transcribed data was analyzed using thematic analysis according to Braun and Clarke.

Results

Staff viewed person-centered care as an approach rather than a method. They described central aspects of person-centered care, such as recognizing the patient as a capable person who can participate in her/his care. Statements further showed how these core features were put into practice. Changes related to the intervention were presented in terms of evolving patient and staff roles, improved contact with patients, more flexible care routines, and a more positive ward climate. Neither psychotic symptoms nor involuntary status were considered barriers for person-centered care, but organizational factors beyond staff control seemed to impact on implementation.

Conclusions

After implementation, participants displayed good understanding of the core concepts of person-centered care in both thinking and action. They attributed several improvements in the care milieu to an increased level of person-centeredness. Psychotic behavior and involuntary treatment did not present major barriers to person-centered care. Findings suggest person-centered care is feasible in the psychosis inpatient setting and could improve quality of care.

Trial registration

The study is part of a larger study evaluating the intervention Person-Centered Psychosis Care (PCPC). It was registered retrospectively at clinicaltrials.gov, identifier NCT03182283.
The effects of SARS-CoV-2 infection on modulating innate immunity and strategies of combating inflammatory response for COVID-19 therapy
Authors: Wang Yiran , Wu Mandi , Li Yichen , Yuen Ho Him , He Ming-Liang
Published: May 2022

The global pandemic of COVID-19 has caused huge causality and unquantifiable loss of social wealth. The innate immune response is the first line of defense against SARS-CoV-2 infection. However, strong inflammatory response associated with dysregulation of innate immunity causes severe acute respiratory syndrome (SARS) and death. In this review, we update the current knowledge on how SARS-CoV-2 modulates the host innate immune response for its evasion from host defense and its corresponding pathogenesis caused by cytokine storm. We emphasize Type I interferon response and the strategies of evading innate immune defense used by SARS-CoV-2. We also extensively discuss the cells and their function involved in the innate immune response and inflammatory response, as well as the promises and challenges of drugs targeting excessive inflammation for antiviral treatment. This review would help us to figure out the current challenge questions of SARS-CoV-2 infection on innate immunity and directions for future studies.
Combining photo-elicitation and discourse analysis to examine adolescents’ sexuality in rural Zambia
Authors: Mulubwa Chama , Hurtig Anna-Karin , Zulu Joseph Mumba , Michelo Charles , Sandøy Ingvild Fossgard , Goicolea Isabel
Published: May 2022

Introduction

This article aimed to analyse constructions of adolescents’ sexualities and sexual health and the consequences of these discourses for adolescents’ exercise of their sexual reproductive health and rights (SRHR) in rural Zambia.

Methods

Interpretative repertoires, which is rooted in discursive psychology was used to analyse data from photo-elicitations interviews and focus group discussions. Our participants included 25 adolescents who participated in a SRHR intervention that aimed to reduce adolescents’ pregnancies and early marriages.

Results

We identified three interpretative repertories: 1) sex is for mature people in which adolescents positioned themselves as ‘immature, and young to engage in sex; 2) gendered respectful behaviours in which what was considered disrespectful (and respectful) behaviour in relation to sexuality were strongly influenced by gender, and more clearly defined for girls than it was for boys. Sexuality was not only about individual choices but about being respectful to parents; and 3) acquiring and using knowledge about sexuality in which adolescents conflicted between having and applying SRHR knowledge.

Conclusion

These repertories offer an important context that shape how adolescents negotiate, adopt and resist SRHR interventions. Future interventions that target adolescents’ SRHR must aim to address the sexual scripts that serve to erect barriers against positive sexual behaviours, including access to SRHR services that promote safer sex.
Impacts of dietary exposure to pesticides on faecal microbiome metabolism in adult twins
Authors: Mesnage Robin , Bowyer Ruth C. E. , El Balkhi Souleiman , Saint-Marcoux Franck , Gardere Arnaud , Ducarmon Quinten Raymond , Geelen Anoecim Robecca , Zwittink Romy Daniëlle , Tsoukalas Dimitris , Sarandi Evangelia , Paramera Efstathia I. , Spector Timothy , Steves Claire J. , Antoniou Michael N.
Published: May 2022

Background

Dietary habits have a profound influence on the metabolic activity of gut microorganisms and their influence on health. Concerns have been raised as to whether the consumption of foodstuffs contaminated with pesticides can contribute to the development of chronic disease by affecting the gut microbiome. We performed the first pesticide biomonitoring survey of the British population, and subsequently used the results to perform the first pesticide association study on gut microbiome composition and function from the TwinsUK registry.

Methods

Dietary exposure of 186 common insecticide, herbicide, or fungicide residues and the faecal microbiome in 65 twin pairs in the UK was investigated. We evaluated if dietary habits, geographic location, or the rural/urban environment, are associated with the excretion of pesticide residues. The composition and metabolic activity of faecal microbiota was evaluated using shotgun metagenomics and metabolomics respectively. We performed a targeted urine metabolomics analysis in order to evaluate whether pesticide urinary excretion was also associated with physiological changes.

Results

Pyrethroid and/or organophosphorus insecticide residues were found in all urine samples, while the herbicide glyphosate was found in 53% of individuals. Food frequency questionnaires showed that residues from organophosphates were higher with increased consumption of fruit and vegetables. A total of 34 associations between pesticide residue concentrations and faecal metabolite concentrations were detected. Glyphosate excretion was positively associated with an overall increased bacterial species richness, as well as to fatty acid metabolites and phosphate levels. The insecticide metabolite Br2CA, reflecting deltamethrin exposure, was positively associated with the phytoestrogens enterodiol and enterolactone, and negatively associated with some N-methyl amino acids. Urine metabolomics performed on a subset of samples did not reveal associations with the excretion of pesticide residues.

Conclusions

The consumption of conventionally grown fruit and vegetables leads to higher ingestion of pesticides with unknown long-term health consequences. Our results highlight the need for future dietary intervention studies to understand effects of pesticide exposure on the gut microbiome and possible health consequences.
What are the short-term annual cost savings associated with kidney transplantation?
Authors: Koto Prosper , Tennankore Karthik , Vinson Amanda , Krmpotic Kristina , Weiss Matthew J. , Theriault Chris , Beed Stephen
Published: May 2022

Background

Kidney transplantation (KT) is often reported in the literature as associated with cost savings. However, existing studies differ in their choice of comparator, follow-up period, and the study perspective. Also, there may be unobservable heterogeneity in health care costs in the patient population which may divide the population into groups with differences in cost distributions. This study estimates the cost savings associated with KT from a payer perspective and identifies and characterizes both high and low patient cost groups.

Method

The current study was a population-based retrospective before-and-after study. The timespan involved at most three years before and after KT. The sample included end-stage kidney disease patients in Nova Scotia, a province in Canada, who had a single KT between January 1, 2011, and December 31, 2018. Each patient served as their control. The primary outcome measure was total annual health care costs. We estimated cost savings using unadjusted and adjusted models, stratifying the analyses by donor type. We quantified the uncertainty around the estimates using non-parametric and parametric bootstrapping. We also used finite mixture models to identify data-driven cost groups based on patients’ pre-transplantation annual inpatient costs.

Results

The mean annual cost savings per patient associated with KT was $19,589 (95% CI: $14,013, $23,397). KT was associated with a 24–29% decrease in mean annual health care costs per patient compared with the annual costs before KT. We identified and characterized patients in three cost groups made of 2.9% in low-cost (LC), 51.8% in medium-cost (MC) and 45.3% in high-cost (HC). Cost group membership did not change after KT. Comparing costs in each group before and after KT, we found that KT was associated with 17% mean annual cost reductions for the LC group, 24% for the MC group and 26% for the HC group. The HC group included patients more likely to have a higher comorbidity burden (Charlson comorbidity index ≥ 3).

Conclusions

KT was associated with reductions in annual health care costs in the short term, even after accounting for costs incurred during KT.
Disability burden due to musculoskeletal conditions and low back pain in Australia: findings from GBD 2019
Authors: de Luca Katie , Briggs Andrew M. , French Simon D. , Ferreira Manuela L. , Cross Marita , Blyth Fiona , March Lyn
Published: May 2022

Background

To report the national prevalence, years lived with disability (YLDs) and attributable risk factors for all musculoskeletal conditions and separately for low back pain (LBP), as well as compare the disability burden related to musculoskeletal with other health conditions in Australia in 2019.

Methods

Global Burden of Disease (GBD) 2019 study meta-data on all musculoskeletal conditions and LBP specifically were accessed and aggregated. Counts and age-standardised rates, for both sexes and across all ages, for prevalence, YLDs and attributable risk factors are reported.

Results

In 2019, musculoskeletal conditions were estimated to be the leading cause of YLDs in Australia (20.1%). There were 7,219,894.5 (95% UI: 6,847,113–7,616,567) prevalent cases of musculoskeletal conditions and 685,363 (95% UI: 487,722–921,471) YLDs due to musculoskeletal conditions. There were 2,676,192 (95% UI: 2,339,327–3,061,066) prevalent cases of LBP and 298,624 (95% UI: 209,364–402,395) YLDs due to LBP. LBP was attributed to 44% of YLDs due to musculoskeletal conditions. In 2019, 22.3% and 39.8% of YLDs due to musculoskeletal conditions and LBP, respectively, were attributed to modifiable GBD risk factors.

Conclusions

The ongoing high burden due to musculoskeletal conditions impacts Australians across the life course, and in particular females and older Australians. Strategies for integrative and organisational interventions in the Australian healthcare system should support high-value care and address key modifiable risk factors for disability such as smoking, occupational ergonomic factors and obesity.
Activation of the viral sensor oligoadenylate synthetase 2 (Oas2) prevents pregnancy-driven mammary cancer metastases
Authors: Ho Wing-Hong Jonathan , Law Andrew M. K. , Masle-Farquhar Etienne , Castillo Lesley E. , Mawson Amanda , O’Bryan Moira K. , Goodnow Christopher C. , Gallego-Ortega David , Oakes Samantha R. , Ormandy Christopher J.
Published: May 2022

Background

The interferon response can influence the primary and metastatic activity of breast cancers and can interact with checkpoint immunotherapy to modulate its effects. UsingN-ethyl-N-nitrosourea mutagenesis, we found a mouse with an activating mutation in oligoadenylate synthetase 2 (Oas2), a sensor of viral double stranded RNA, that resulted in an interferon response and prevented lactation in otherwise healthy mice.

Methods

To determine if sole activation ofOas2could alter the course of mammary cancer, we combined theOas2mutation with theMMTV-PyMToncogene model of breast cancer and examined disease progression and the effects of checkpoint immunotherapy using Kaplan–Meier survival analysis with immunohistochemistry and flow cytometry.

Results

Oas2mutation prevented pregnancy from increasing metastases to lung. Checkpoint immunotherapy with antibodies against programmed death-ligand 1 was more effective when theOas2mutation was present.

Conclusions

These data establish OAS2 as a therapeutic target for agents designed to reduce metastases and increase the effectiveness of checkpoint immunotherapy.
Hereditary angioedema due to C1 inhibitor deficiency: real-world experience from the Icatibant Outcome Survey in Spain
Authors: Guilarte Mar , Sala-Cunill Anna , Baeza María Luisa , Cabañas Rosario , Hernández María Dolores , Ibañez Ethel , de Larramendi Carlos Hernando , Lleonart Ramon , Lobera Teófilo , Marqués Luis , de San Pedro Blanca Sáenz , Botha Jaco , Andresen Irmgard , Caballero Teresa ,   for the IOS Study Group
Published: May 2022

Background

The Icatibant Outcome Survey (IOS) is an international registry monitoring the use of icatibant, a bradykinin B2 receptor antagonist indicated for the acute treatment of hereditary angioedema (HAE) attacks. Our goal was to assess disease characteristics and icatibant treatment outcomes in patients with HAE due to C1 inhibitor deficiency (HAE type 1 or 2 (HAE-1/2)) from Spain relative to other countries participating in IOS.

Methods

Descriptive retrospective analyses of data are reported from 10 centers in Spain vs 51 centers in 12 other participating countries (July 2009 to January 2019).

Results

No meaningful differences were identified between patients in Spain (n = 119) and patients across other countries (n = 907) regarding median age at symptom onset (15.0 vs 12.0 years) or diagnosis (22.3 vs 20.5 years). Overall HAE attack rates (total attacks/total years of follow-up) were 2.66 in Spain and 1.46 across other countries. Patients in Spain reported fewer severe/very severe HAE attacks before treatment (41.0% vs 45.9%; P < 0.0001) and, for icatibant-treated attacks, longer median time to treatment (2.9 vs 1.0 h), time to attack resolution (18.0 vs 5.5 h), and total attack duration (24.6 vs 8.0 h). Use of androgens for long-term prophylaxis was higher in Spain (51.2% vs 26.7%).

Conclusion

Patients with HAE-1/2 in Spain reported fewer severe/very severe attacks, administered icatibant later, and had longer-lasting attacks than did patients across other countries in IOS. These differences may indicate varying disease management practices (e.g., delayed icatibant treatment) and reporting. Efforts to raise awareness on the benefits of early on-demand treatment may be warranted.

Trial registration: NCT01034969.
Cell membrane fluidity and ROS resistance define DMSO tolerance of cryopreserved synovial MSCs and HUVECs
Authors: Mizuno Mitsuru , Matsuzaki Takahisa , Ozeki Nobutake , Katano Hisako , Koga Hideyuki , Takebe Takanori , Yoshikawa Hiroshi Y. , Sekiya Ichiro
Published: May 2022

Objectives

Synovial mesenchymal stem cells (MSCs) have high freeze–thaw tolerance, whereas human umbilical vein endothelial cells (HUVECs) have low freezing tolerance. The differences in cell type-specific freeze–thaw tolerance and the mechanisms involved are unclear. This study thus aimed to identify the biological and physical factors involved in the differences in freeze–thaw tolerance between MSCs and HUVECs.

Materials and methods

For biological analysis, MSC and HUVEC viability after freeze-thawing and alteration of gene expression in response to dimethyl sulfoxide (DMSO, a cryoprotectant) were quantitatively evaluated. For physical analysis, the cell membrane fluidity of MSCs and HUVECs before and after DMSO addition was assessed using a histogram for generalized polarization frequency.

Results

HUVECs showed lower live cell rates and higher gene expression alteration related to extracellular vesicles in response to DMSO than MSCs. Fluidity measurements revealed that the HUVEC membrane was highly fluidic and sensitive to DMSO compared to that of MSCs. Addition of CAY10566, an inhibitor of stearoyl-coA desaturase (SCD1) that produces highly fluidic desaturated fatty acids, decreased the fluidity of HUVECs and increased their tolerance to DMSO. The combination of CAY10566 and antioxidant glutathione (GSH) treatment improved HUVEC viability from 57 to 69%. Membrane fluidity alteration may thus contribute to pore-induced DMSO influx into the cytoplasm and reactive oxygen species production, leading to greater cytotoxicity in HUVECs, which have low antioxidant capacity.

Conclusions

Differences in freeze–thaw tolerance originate from differences in the cell membranes with respect to fluidity and antioxidant capacity. These findings provide a basis for analyzing cell biology and membrane-physics to establish appropriate long-term preservation methods aimed at promoting transplantation therapies.
LncRNAs and their RBPs: How to influence the fate of stem cells?
Authors: Zhao Cong , Xie Wen , Zhu Hecheng , Zhao Ming , Liu Weidong , Wu Zhaoping , Wang Lei , Zhu Bin , Li Shasha , Zhou Yao , Jiang Xingjun , Xu Qiang , Ren Caiping
Published: May 2022

Stem cells are distinctive cells that have self-renewal potential and unique ability to differentiate into multiple functional cells. Stem cell is a frontier field of life science research and has always been a hot spot in biomedical research. Recent studies have shown that long non-coding RNAs (lncRNAs) have irreplaceable roles in stem cell self-renewal and differentiation. LncRNAs play crucial roles in stem cells through a variety of regulatory mechanisms, including the recruitment of RNA-binding proteins (RBPs) to affect the stability of their mRNAs or the expression of downstream genes. RBPs interact with different RNAs to regulate gene expression at transcriptional and post-transcriptional levels and play important roles in determining the fate of stem cells. In this review, the functions of lncRNAs and their RBPs in self-renewal and differentiation of stem cell are summarized. We focus on the four regulatory mechanisms by which lncRNAs and their RBPs are involved in epigenetic regulation, signaling pathway regulation, splicing, mRNA stability and subcellular localization and further discuss other noncoding RNAs (ncRNAs) and their RBPs in the fate of stem cells. This work provides a more comprehensive understanding of the roles of lncRNAs in determining the fate of stem cells, and a further understanding of their regulatory mechanisms will provide a theoretical basis for the development of clinical regenerative medicine.
Mesenchymal stem cell homing to improve therapeutic efficacy in liver disease
Authors: Yuan Mengqin , Hu Xue , Yao Lichao , Jiang Yingan , Li Lanjuan
Published: May 2022

Mesenchymal stem cell (MSC) transplantation, as an alternative strategy to orthotopic liver transplantation, has been evaluated for treating end-stage liver disease. Although the therapeutic mechanism of MSC transplantation remains unclear, accumulating evidence has demonstrated that MSCs can regenerate tissues and self-renew to repair the liver through differentiation into hepatocyte-like cells, immune regulation, and anti-fibrotic mechanisms. Multiple clinical trials have confirmed that MSC transplantation restores liver function and alleviates liver damage. A sufficient number of MSCs must be home to the target tissues after administration for successful application. However, inefficient homing of MSCs after systemic administration is a major limitation in MSC therapy. Here, we review the mechanisms and clinical application status of MSCs in the treatment of liver disease and comprehensively summarize the molecular mechanisms of MSC homing, and various strategies for promoting MSC homing to improve the treatment of liver disease.
Treating intrauterine adhesion using conditionally reprogrammed physiological endometrial epithelial cells
Authors: Xia Siyu , Wu Ming , Zhou Xinhao , Zhang Xiu , Ye Lina , Zhang Kang , Kang Yiyi , Liu Jun , Zhang Yunci , Wu Wang , Dong Dirong , Chen Hong , Li Hui
Published: May 2022

Background

There is unmet need for effective therapies of intrauterine adhesions (IUAs) that are common cause of menstrual disturbance and infertility, since current clinical procedures do not improve prognosis for patients with moderate to severe IUA, with a recurrence rate of 23–50%. Stem cell-based therapy has emerged as a therapeutic option with unsolved issues for IUA patients in the past few years. Primary endometrial epithelial cells for cell therapy are largely hampered with the extremely limited proliferation capacity of uterine epithelial cells. This study was to evaluate whether IUA is curable with conditionally reprogrammed (CR) endometrial epithelial cells.

Methods

Mouse endometrial epithelial cells (MEECs) were isolated from C57BL female mice, and long-term cultures of MEECs were established and maintained with conditional reprogramming (CR) method. DNA damage response analysis, soft agar assay, and matrigel 3D culture were carried out to determine the normal biological characteristics of CR-MEECs. The tissue-specific differentiation potential of MEECs was analyzed with air–liquid interface (ALI) 3D culture, hematoxylin and eosin (H&E) staining, Masson’s trichrome and DAB staining, immunofluorescence assay. IUA mice were constructed and transplanted with CR-MEECs. Repair and mechanisms of MEECs transplantation in IUA mice were measured with qRT-PCR, Masson’s trichrome, and DAB staining.

Results

We first successfully established long-term cultures of MEECs using CR approach. CR-MEECs maintained a rapid and stable proliferation in this co-culture system. Our data confirmed that CR-MEECs retained normal biological characteristics and endometrium tissue-specific differentiation potential. CR-MEECs also expressed estrogen and progesterone receptors and maintained the exquisite sensitivity to sex hormones in vitro. Most importantly, allogeneic transplantation of CR-MEECs successfully repaired the injured endometrium and significantly improved the pregnancy rate of IUA mice.

Conclusions

Conditionally reprogrammed physiological endometrial epithelial cells provide a novel strategy in IUA clinics in a personalized or generalized manner and also serve as a physiological model to explore biology of endometrial epithelial cells and mechanisms of IUA.
The sodium iodide symporter (NIS) as theranostic gene: its emerging role in new imaging modalities and non-viral gene therapy
Authors: Kitzberger Carolin , Spellerberg Rebekka , Morath Volker , Schwenk Nathalie , Schmohl Kathrin A. , Schug Christina , Urnauer Sarah , Tutter Mariella , Eiber Matthias , Schilling Franz , Weber Wolfgang A. , Ziegler Sibylle , Bartenstein Peter , Wagner Ernst , Nelson Peter J. , Spitzweg Christine
Published: May 2022

Cloning of the sodium iodide symporter (NIS) in 1996 has provided an opportunity to use NIS as a powerful theranostic transgene. Novel gene therapy strategies rely on image-guided selective NIS gene transfer in non-thyroidal tumors followed by application of therapeutic radionuclides. This review highlights the remarkable progress during the last two decades in the development of the NIS gene therapy concept using selective non-viral gene delivery vehicles including synthetic polyplexes and genetically engineered mesenchymal stem cells. In addition, NIS is a sensitive reporter gene and can be monitored by high resolution PET imaging using the radiotracers sodium [124I]iodide ([124I]NaI) or [18F]tetrafluoroborate ([18F]TFB). We performed a small preclinical PET imaging study comparing sodium [124I]iodide and in-house synthesized [18F]TFB in an orthotopic NIS-expressing glioblastoma model. The results demonstrated an improved image quality using [18F]TFB. Building upon these results, we will be able to expand the NIS gene therapy approach using non-viral gene delivery vehicles to target orthotopic tumor models with low volume disease, such as glioblastoma.

Trial registration not applicable.