bluuebunny/crossref_metadata_2025 huggingface dataset:
Study of aqueous humour inflammatory mediators’ levels in a cohort of Egyptian patients with diabetic macular oedema
Authors: Gomaa Amir Ramadan , Bedda Ahmed Magdy , ElGoweini Hesham Fouad , Taleb Raghda Saad Zaghloul , Saleh Ahmed Mahmoud Abdelrahman
Published: November 2023

Background

The aim was to study aqueous humour inflammatory mediators’ levels in a cohort of Egyptian patients with diabetic macular oedema (DMO).

Methods

This was a case-control prospective study conducted on 2 groups: 25 eyes of 22 (11 females) patients seeking treatment for DMO as patients group, and 10 eyes of 10 (4 females) cataract patients as a control group. Aqueous humour was aspirated before intravitreal injection (patients’ group) or cataract surgery (control group). Inflammatory mediators in aqueous humour were measured using a multiplex bead immunoassay kit of 27 pre-mixed cytokines.

Results

Eotaxin, interferon gamma-induced protein 10 (IP-10), monocyte chemoattractant protein-1 (MCP-1/CCL2) and interleukin-8 (IL-8/CXCL8) were found significantly higher in patients’ group compared to control group (p = 0.043, 0.037, 0.001, 0.015 respectively). On the contrary, interferon-gamma (IFN-gamma) and granulocyte colony-stimulating factor (G-CSF) were found significantly higher in control group than patients’ group (p = 0.003, 0.019 respectively). Basic fibroblast growth factor (Basic-FGF/FGF-2) and interleukin-1 receptor antagonist (IL-1ra) were found higher (but not statistically significant) in controls (p = 0.100 and 0.070 respectively). Additionally, a negative and significant correlation was found between Eotaxin level in aqueous humour and central macular thickness.

Conclusions

Some mediators might be implicated in the pathogenesis of DMO either augmenting or suppressing role. Eotaxin, IP-10, MCP-1 and IL-8 might have a role in cases not responding to standard anti-vascular endothelial growth factor (VEGF) therapy. IL-1ra might have a protective role; therefore, the effectiveness of intravitreal injection of IL-1ra homologue needs to be studied in future clinical trials.
Life experienced as worth living and beyond: a qualitative study of the pathways to recovery and flourishing amongst individuals treated for borderline personality disorder
Authors: Liljedahl Sophie I. , Mossberg Anni , Grenner Hanna , Waern Margda
Published: November 2023

Background

Dialectical Behaviour Therapy (DBT) is recognized as a leading evidence-based treatment, effective in reducing symptoms of borderline personality disorder (BPD), as well as co-occurring clinical syndromes. However, symptom remission may not be the same as a life experienced as worth living. The purpose of the study was to understand, from the perspective of individuals with lived experience, the concepts of recovery, life experienced as worth living and flourishing after treatment for BPD, and to describe the pathways to wellness after symptom remission.

Methods

Semi-structured interviews were conducted with nine adult women previously diagnosed with BPD, co-occurring clinical syndromes and severe self-harm behaviour who self-identified as recovered for a minimum of two years, recruited from a network for individuals with lived experience. The average duration of recovery was 5.7 years with a range from 2 to 10 + years. Data were analysed using thematic analysis.

Results

Four main themes and 14 subthemes were generated from our analyses. Main themes indicated that loved ones helped recovery and to create a life worth living, that participants identified as recovered and as healthy and beyond, and that becoming well is a long process associated in part with reclaiming a healthy identity. Participants defined recovery as separate but related to a life worth living, which in turn was separate but related to being healthy and having lives they described as being beyond health and well-being. The wellness process was described as lengthy and non-linear, including setbacks that with time no longer derailed daily life. A proposed theoretical model depicting the wellness process over time from symptom remission to the experience of a life beyond health and wellness is presented.

Conclusions

This qualitative study contributes knowledge of what a life experienced as worth living means, as well as how wellness progressed into flourishing for some participants within a sample of individuals with lived experience. Our findings may inform treatment development that targets more than symptom reduction, which in turn may shorten trajectories from symptom remission to health, wellness, and flourishing.
The effect of ambient air pollution on birth outcomes in Norway
Authors: Ling Xiaoguang
Published: November 2023

Background

Ambient air pollution can be harmful to the fetus even in countries with relatively low levels of pollution. Most of the established literature estimates the association between air pollution and health rather than causality. In this paper, I examine the causal effects of ambient air pollution on birth outcomes in Norway.

Methods

With the large sample size and geographic division of sub-postal codes in Norway, I can control for a rich set of spatio-temporal fixed effects to overcome most of the endogeneity problems caused by the choice of residential area and date of delivery. After controlling for a rich set of spatio-temporal fixed effects, my paper uses the variance in ambient air pollutant concentrations over narrow time intervals and in a small geographic area of Norway to determine how prenatal air pollution exposure affects birth outcomes. My data contain extensive information about parents as well as meteorological conditions that can be used to control for potential confounding factors.

Results

I find that prenatal exposure to ambient nitric oxide in the last trimester causes significant birth weight and birth length loss under the same sub-postcode fixed effects and calendar month fixed effects, whereas other ambient air pollutants such as nitrogen dioxide and sulfur dioxide appear to be at safe levels for the fetus in Norway. In addition, the marginal adverse effect of ambient nitric oxide is larger for newborns with disadvantaged parents. Both average concentrations of nitric oxide and occasional high concentration events can adversely affect birth outcomes.

Conclusions

Prenatal exposure to NO pollution has an adverse effect on birth outcomes. This suggests that government and researchers should pay more attention to examining NO pollution and that health care providers need to advise pregnant women about the risks of air pollution during pregnancy.
Protocol of a cluster randomised trial of BodyKind: a school-based body image programme for adolescents
Authors: Mahon Ciara , Hamburger Denise , Webb Jennifer B. , Yager Zali , Howard Emma , Booth Ailbhe , Fitzgerald Amanda
Published: November 2023

Background

Poor body image is prevalent among adolescents and associated with several negative outcomes for their physical and psychological health. There is a pressing need to address this growing public health concern, yet there are few evidence-informed universal programmes for older adolescents that address contemporary body image concerns (i.e., social media). BodyKind is a four lesson, school-based, teacher led, universal body image programme that incorporates empirically supported principles of cognitive dissonance, self-compassion, compassion for others and social activism, to support positive body image development. Building on previous pilot trials in the USA, this paper outlines the protocol for a cluster randomised control trial (cRCT) and implementation evaluation of the BodyKind programme which was culturally adapted for the Irish cultural context.

Methods

We aim to recruit 600 students aged 15-17 years in Transition Year (4th year) across 26 second-level schools in Ireland. Using minimisation, schools will be randomly assigned to receive BodyKind (intervention condition, n=300) or classes as usual (waitlist control, n=300). Teachers in intervention groups will receive training and deliver the programme to students over four weeks, at a rate of one lesson per week. Primary outcomes of body appreciation, body dissatisfaction and psychological wellbeing and secondary outcomes of self-compassion, compassion for others, body ideal internalisation, social justice motives and appearance-based social media use will be assessed at pre-, post- and 2 month follow up. Mediation and moderation analyses will be conducted to identify how and for whom the intervention works best. An implementation evaluation will assess the quality of programme implementation across schools and how this may influence intervention outcomes. Waitlist control schools will receive the programme after the 2-month follow up.

Conclusion

This study will be the first to implement a cRCT and an implementation evaluation to assess the impact of this multicomponent school-based body image programme designed to support healthy body image development. If shown to be effective, BodyKind will have the potential to improve adolescent body image and wellbeing and inform efforts to implement sustainable and scalable programmes in schools.

Trial registration

The trial was retrospectively registered on 10/10/2023 on ClinicalTrials.gov NCT06076993.
Trends in deaths and disability-adjusted life-years of stroke attributable to low physical activity worldwide, 1990–2019
Authors: Li Jun-xiao , Zhong Qiong-qiong , Yuan Shi-xiang , Zhu Feng
Published: November 2023

Background

Low physical activity (LPA) is linked to the risk of stroke, but the disease burden of stroke attributable to LPA needs to be understood to develop effective preventive strategies. We aim to assess spatiotemporal trends in the global burden of stroke attributable to LPA from 1990 to 2019.

Methods

Based on the Global Burden of Disease, Injuries, and Risk Factors Study, our research examined deaths, the Disability-Adjusted Life Years (DALYs), the Age-Standardized Mortality Rate (ASMR), the Age-Standardized DALY Rate (ASDR), and the Estimated Annual Percentage Change (EAPC) for stroke attributable to LPA.

Results

Deaths and DALYs were on the rise worldwide from 1990 to 2019, with increases of 72.72% for the former and 67.41% for the latter; ASMR and ASDR decreased, with the ASMR-related EAPC of -1.61 (95% CI:-1.71–-1.5) and ASDR-related EAPC of -1.35 (95% CI:-1.43–-1.27); females had more numbers of deaths and DALYs, and the majorities of deaths and DALYs were shared by those aged ≥ 70. The highest burden rates were shared by North Africa, the Middle East, and Tropical Latin America; the ASMR-related EAPC was associated with the ASMR in 1990 (R = -0.26, P < 0.001) and the Socio-Demographic Index (SDI) across different countries in 2019 (R = -0.61, P < 0.001), respectively, and such patterns were similar to what ASDR and the ASDR-related EAPC had; the Human Development Index (HDI) in 2019 was associated with the ASMR-related EAPC (R = 0.63, P < 0.001) and the ASDR-related EAPC across different countries (R = -0.62, P < 0.001), respectively.

Conclusions

Globally, deaths and DALYs of stroke attributable to LPA were on the rise, although their age-standardized rates presented downward over the past three decades; the burden of stroke attributable to LPA showed upward trends especially in those aged ≥ 70 and females in the regions of East Asia, North Africa, and the Middle East, which need more attention to the effects of physical activity on health interventions.
Racial disparities between measures of area deprivation and financial toxicity, and uterine volume in myomectomy patients
Authors: Bossick Andrew S. , Abood Joelle Aoun , Oaks Ashlee , Vilkins Annmarie , Shukr Ghadear , Chamseddine Petra , Wegienka Ganesa R.
Published: November 2023

Background

At time of myomectomy, a surgical procedure to remove uterine fibroids, Black women tend to have larger uteri than White women. This makes Black patients less likely to undergo a minimally invasive myomectomy which has been shown to have less postoperative pain, less frequent postoperative fever and shorter length of stay compared to abdominal myomectomies. The associations between individual financial toxicity and community area deprivation and uterine volume at the time of myomectomy have not been investigated.

Methods

We conducted a secondary data analysis of patients with fibroids scheduled for myomectomy using data from a fibroid treatment registry in [location]. We used validated measures of individual-level Financial Toxicity (higher scores = better financial status) and community-level Area Deprivation (ADI, high scores = worse deprivation). To examine associations with log transformed uterine volume, we used linear regression clustered on race (Black vs. White).

Results

Black participants had worse financial toxicity, greater deprivation and larger uterine volumes compared with White participants. A greater Financial Toxicity score (better financial status) was associated with lower uterine volume. For every 10 unit increase in Financial Toxicity, the mean total uterine volume decreased by 9.95% (Confidence Interval [CI]: -9.95%, -3.99%). ADI was also associated with uterine volume. A single unit increase in ADI (worse deprivation) was associated with a 5.13% (CI: 2.02%, 7.25%) increase in mean uterine volume.

Conclusion

Disproportionately worse Financial Toxicity and ADI among Black patients is likely due to structural racism – which now must be considered in gynecologic research and practice.

Trial Registration

Not applicable.
Women’s experiences of psychological treatment and psychosocial interventions for postpartum depression: a qualitative systematic review and meta-synthesis
Authors: Massoudi Pamela , Strömwall Leif A. , Åhlen Johan , Kärrman Fredriksson Maja , Dencker Anna , Andersson Ewa
Published: November 2023

Background

To provide a comprehensive, systematic evaluation of the literature on experiences of psychological interventions for postpartum depression (PPD) in women. Depression is one of the most common postpartum mental disorders. Studies have identified that psychological interventions reduce depressive symptoms. However, less is known about the experiences of women who have received such treatments.

Methods

A systematic review of the literature was conducted by searching five databases (CINAHL, Cochrane Library, EMBASE, Medline, PsycINFO), in August 2022. Studies with qualitative methodology examining women’s experiences of professional treatment for PPD were included and checked for methodological quality. Eight studies (total N = 255) contributed to the findings, which were synthesized using thematic synthesis. Confidence in the synthesized evidence was assessed with GRADE CERQual.

Findings

The women had received cognitive behavioral therapy (5 studies) or supportive home visits (3 studies). Treatments were individual or group-based. Two main themes were identified: Circumstances and expectations, and Experiences of treatment, with six descriptive themes. Establishing a good relationship to their health professional was important for the women, regardless of treatment model. They also expressed that they wanted to be able to choose the type and format of treatment. The women were satisfied with the support and treatment received and expressed that their emotional well-being had been improved as well as the relationship to their infant.

Conclusion

The findings can be helpful to develop and tailor patient-centered care for women who are experiencing postnatal depression.
Clomiphene citrate plus letrozole versus clomiphene citrate alone for ovulation induction in infertile women with ovulatory dysfunction: a randomized controlled trial
Authors: Chera-aree Pattraporn , Tanpong Sirikul , Thanaboonyawat Isarin , Laokirkkiat Pitak
Published: November 2023

Background

The aim of this study was to compare the efficacy of the combination of clomiphene citrate (CC) and letrozole to that of CC alone in inducing ovulation in infertile women with ovulatory dysfunction.

Methods

A randomized controlled trial was conducted at a single academic medical center between November 2020 and December 2021. Anovulatory infertility females, aged 18 to 40, were evenly distributed by a computer-generated block of four into two treatment groups. A “combination group” received a daily dose of CC (50 mg) and letrozole (2.5 mg), while a “CC-alone group” received a daily dose of CC alone (50 mg). The study medications were administered on days 3 through 7 of menstrual cycle. The primary outcome was the ovulation rate, defined by serum progesterone levels exceeding 3 ng/mL at the mid-luteal phase. The secondary outcomes were ovulation induction cycle characteristics, endometrial thickness, conception rate, and adverse events.

Results

One hundred women (50 per group) were enrolled in the study. The mean age was not significantly different in both groups: 31.8 years in the combination group and 32.4 years in the CC-alone groups (P = 0.54). The prevalence of polycystic ovary syndrome in the combination and CC-alone groups was 48% and 44%, respectively (P = 0.841). According to intention-to-treat analysis, the ovulation rates were 78% and 70% in the combination and CC-alone groups, respectively (P > 0.05). There was no significant difference in the mean endometrial thickness or the number of dominant follicles of the groups. No serious adverse events were observed in either group.

Conclusions

Our study found no significant difference between the combination of CC and letrozole and CC alone in inducing ovulation in infertile women with ovulatory dysfunction in one cycle. The small number of live births precluded any meaningful statistical analysis. Further studies are needed to validate and extend our findings beyond the scope of the current study.

Trial registration

The study was registered at https://www.thaiclinicaltrials.org with the following number: TCTR20201108004 and was approved on 08/11/2020.
Self-management challenges and support needs among patients with primary glaucoma: a qualitative study
Authors: Hua Yiting , LU Hujie , Dai Jingyao , Zhou Yewei , Zhou Wenzhe , Wang Aisun , Chen Yanyan , Liang Youping
Published: November 2023

Background

Self-management plays an important role in the disease management of glaucoma patients. The effectiveness of the program can be improved by assessing the patient’s perspective and needs to tailor self-management support. Most studies have focused on assessing one of these self-management behaviours, such as medication adherence, and there is a lack of systematic assessment of the support needs and challenges of self-management for patients with glaucoma. Therefore, in this study, we conducted an in-depth investigation into the self-management challenges and support needs of patients with primary glaucoma, providing a basis for nursing staff to implement self-management support.

Method

The phenomenological method and semistructured interviews were used in this study. A total of 20 patients with primary glaucoma were recruited between June and December 2022. Colaizzi’s analysis method was used to analyse the interview data.

Results

Challenges for patients include becoming an expert in glaucoma, managing negative emotions, adapting to daily life changes and resuming social activities. To address these challenges, four themes of patient self-management support needs were identified: (1) health information support, (2) social support, (3) psychological support, and (4) daily living support.

Conclusion

Patients with primary glaucoma experience varying degrees of challenge in dealing with medical, emotional, and social aspects. Comprehending the support needs of patients, healthcare professionals should deliver targeted, personalized and comprehensive self-management interventions to enhance their capacity of patients to perform self-management and improve their quality of life.
A mathematical model of Marburg virus disease outbreaks and the potential role of vaccination in control
Authors: Qian George Y. , Edmunds W. John , Bausch Daniel G. , Jombart Thibaut
Published: November 2023

Background

Marburg virus disease is an acute haemorrhagic fever caused by Marburg virus. Marburg virus is zoonotic, maintained in nature in Egyptian fruit bats, with occasional spillover infections into humans and nonhuman primates. Although rare, sporadic cases and outbreaks occur in Africa, usually associated with exposure to bats in mines or caves, and sometimes with secondary human-to-human transmission. Outbreaks outside of Africa have also occurred due to importation of infected monkeys. Although all previous Marburg virus disease outbreaks have been brought under control without vaccination, there is nevertheless the potential for large outbreaks when implementation of public health measures is not possible or breaks down. Vaccines could thus be an important additional tool, and development of several candidate vaccines is under way.

Methods

We developed a branching process model of Marburg virus transmission and investigated the potential effects of several prophylactic and reactive vaccination strategies in settings driven primarily by multiple spillover events as well as human-to-human transmission. Linelist data from the 15 outbreaks up until 2022, as well as an Approximate Bayesian Computational framework, were used to inform the model parameters.

Results

Our results show a low basic reproduction number which varied across outbreaks, from 0.5 [95% CI 0.05–1.8] to 1.2 [95% CI 1.0–1.9] but a high case fatality ratio. Of six vaccination strategies explored, the two prophylactic strategies (mass and targeted vaccination of high-risk groups), as well as a combination of ring and targeted vaccination, were generally most effective, with a probability of potential outbreaks being terminated within 1 year of 0.90 (95% CI 0.90–0.91), 0.89 (95% CI 0.88–0.90), and 0.88 (95% CI 0.87–0.89) compared with 0.68 (0.67–0.69) for no vaccination, especially if the outbreak is driven by zoonotic spillovers and the vaccination campaign initiated as soon as possible after onset of the first case.

Conclusions

Our study shows that various vaccination strategies can be effective in helping to control outbreaks of MVD, with the best approach varying with the particular epidemiologic circumstances of each outbreak.
Experience of early-life pain in premature infants is associated with atypical cerebellar development and later neurodevelopmental deficits
Authors: Cook Kevin M. , De Asis-Cruz Josepheen , Kim Jung-Hoon , Basu Sudeepta K. , Andescavage Nickie , Murnick Jonathan , Spoehr Emma , Liggett Melissa , du Plessis Adré J. , Limperopoulos Catherine
Published: November 2023

Background

Infants born very and extremely premature (V/EPT) are at a significantly elevated risk for neurodevelopmental disorders and delays even in the absence of structural brain injuries. These risks may be due to earlier-than-typical exposure to the extrauterine environment, and its bright lights, loud noises, and exposures to painful procedures. Given the relative underdeveloped pain modulatory responses in these infants, frequent pain exposures may confer risk for later deficits.

Methods

Resting-state fMRI scans were collected at term equivalent age from 148 (45% male) infants born V/EPT and 99 infants (56% male) born at term age. Functional connectivity analyses were performed between functional regions correlating connectivity to the number of painful skin break procedures in the NICU, including heel lances, venipunctures, and IV placements. Subsequently, preterm infants returned at 18 months, for neurodevelopmental follow-up and completed assessments for autism risk and general neurodevelopment.

Results

We observed that V/EPT infants exhibit pronounced hyperconnectivity within the cerebellum and between the cerebellum and both limbic and paralimbic regions correlating with the number of skin break procedures. Moreover, skin breaks were strongly associated with autism risk, motor, and language scores at 18 months. Subsample analyses revealed that the same cerebellar connections strongly correlating with breaks at term age were associated with language dysfunction at 18 months.

Conclusions

These results have significant implications for the clinical care of preterm infants undergoing painful exposures during routine NICU care, which typically occurs without anesthesia. Repeated pain exposures appear to have an increasingly detrimental effect on brain development during a critical period, and effects continue to be seen even 18 months later.
Is metabolic-healthy obesity associated with risk of dementia? An age-stratified analysis of the Whitehall II cohort study
Authors: Machado-Fragua Marcos D. , Sabia Séverine , Fayosse Aurore , Hassen Céline Ben , van der Heide Frank , Kivimaki Mika , Singh-Manoux Archana
Published: November 2023

Background

Metabolically healthy obesity is hypothesized to be a benign condition but whether this is the case for dementia remains debated. We examined the role of age at assessment of metabolic-obesity phenotypes in associations with incident dementia.

Methods

Obesity (body mass index ≥ 30 kg/m2) and poor metabolic health (≥ 2 of elevated serum triglycerides, low HDL-C, elevated blood pressure, and elevated serum fasting glucose) were used to define four metabolic-obesity phenotypes (metabolically healthy (MHNO) and unhealthy non-obesity (MUNO), metabolically healthy (MHO) and unhealthy obesity (MUO)) at < 60, 60 to < 70, and ≥ 70 years using 6 waves of data from the Whitehall II study and their associations with incident dementia was examined using Cox regression.

Results

Analyses with exposures measured < 60, 60 to < 70, and ≥ 70 years involved 410 (5.8%), 379 (5.6%), and 262 (7.4%) incident dementia cases over a median follow-up of 20.8, 10.3, and 4.2 years respectively. In analyses of individual components, obesity before 60 years (HR 1.41, 95% CI: [1.08, 1.85]) but not at older ages was associated with dementia; unhealthy metabolic status when present < 60 years (HR 1.33, 95% CI: [1.08, 1.62]) and 60 to < 70 years (HR 1.32, 95% CI: [1.07, 1.62]) was associated with dementia. Compared to the metabolically healthy non-obesity group, the risk of dementia was higher in those with metabolically healthy obesity before 60 years (1.69; 95% CI: [1.16, 2.45]); this was not the case when metabolic-obesity phenotype was present at 60 to < 70 years or ≥ 70 years. Analyses at older ages were on smaller numbers due to death and drop-out but inverse probability weighting to account for missing data yielded similar results.

Conclusions

Individuals with metabolically healthy obesity before age 60 had a higher risk of incident dementia over a 27-year follow-up; the excess risk dissipates when metabolic health and obesity are measured after 70 years.
Expression of PD-1/PD-L1 axis in mediastinal lymph nodes and lung tissue of human and experimental lung fibrosis indicates a potential therapeutic target for idiopathic pulmonary fibrosis
Authors: Karampitsakos Theodoros , Galaris Apostolos , Chrysikos Serafeim , Papaioannou Ourania , Vamvakaris Ioannis , Barbayianni Ilianna , Kanellopoulou Paraskevi , Grammenoudi Sofia , Anagnostopoulos Nektarios , Stratakos Grigoris , Katsaras Matthaios , Sampsonas Fotios , Dimakou Katerina , Manali Effrosyni D. , Papiris Spyridon , Tourki Bochra , Juan-Guardela Brenda M , Bakakos Petros , Bouros Demosthenes , Herazo-Maya Jose D , Aidinis Vassilis , Tzouvelekis Argyris
Published: November 2023

Background

Mediastinal lymph node enlargement is prevalent in patients with idiopathic pulmonary fibrosis (IPF). Studies investigating whether this phenomenon reflects specific immunologic activation are lacking.

Methods

Programmed cell death-1 (PD-1)/ programmed cell death ligand-1 (PD-L1) expression in mediastinal lymph nodes and lung tissues was analyzed. PD-1, PD-L1 mRNA expression was measured in tracheobronchial lymph nodes of mice following bleomycin-induced injury on day 14. Finally, the effect of the PD-1 inhibitor, pembrolizumab, in bleomycin-induced pulmonary fibrosis was investigated.

Results

We analyzed mediastinal lymph nodes of thirty-three patients (n = 33, IPF: n = 14, lung cancer: n = 10, concomitant IPF and lung cancer: n = 9) and lung tissues of two hundred nineteen patients (n = 219, IPF: 123, controls: 96). PD-1 expression was increased, while PD-L1 expression was decreased, in mediastinal lymph nodes of patients with IPF compared to lung cancer and in IPF lungs compared to control lungs. Tracheobronchial lymph nodes isolated on day 14 from bleomycin-treated mice exhibited increased size and higher PD-1, PD-L1 mRNA levels compared to saline-treated animals. Pembrolizumab blunted bleomycin-induced lung fibrosis, as indicated by reduction in Ashcroft score and improvement in respiratory mechanics.

Conclusions

Mediastinal lymph nodes of patients with IPF exhibit differential expression profiles than those of patients with lung cancer indicating distinct immune-mediated pathways regulating fibrogenesis and carcinogenesis. PD-1 expression in mediastinal lymph nodes is in line with lung tissue expression. Lower doses of pembrolizumab might exert antifibrotic effects. Clinical trials aiming to endotype patients based on mediastinal lymph node profiling and accordingly implement targeted therapies such as PD-1 inhibitors are greatly anticipated.
COVID-19 induces more pronounced extracellular matrix deposition than other causes of ARDS
Authors: de Souza Xavier Costa Natália , Ribeiro Júnior Gabriel , do Nascimento Ellen Caroline Toledo , de Brito Jôse Mara , Antonangelo Leila , Faria Caroline Silvério , Monteiro Jhonatas Sirino , Setubal João Carlos , Pinho João Renato Rebello , Pereira Roberta Verciano , Seelaender Marilia , de Castro Gabriela Salim , Lima Joanna D. C. C. , de Almeida Monteiro Renata Aparecida , Duarte-Neto Amaro Nunes , Saldiva Paulo Hilário Nascimento , Ferraz da Silva Luiz Fernando , Dolhnikoff Marisa , Mauad Thais
Published: November 2023

Background

Lung fibrosis is a major concern in severe COVID-19 patients undergoing mechanical ventilation (MV). Lung fibrosis frequency in post-COVID syndrome is highly variable and even if the risk is proportionally small, many patients could be affected. However, there is still no data on lung extracellular matrix (ECM) composition in severe COVID-19 and whether it is different from other aetiologies of ARDS.

Methods

We have quantified different ECM elements and TGF-β expression in lung tissue of 28 fatal COVID-19 cases and compared to 27 patients that died of other causes of ARDS, divided according to MV duration (up to six days or seven days or more). In COVID-19 cases, ECM elements were correlated with lung transcriptomics and cytokines profile.

Results

We observed that COVID-19 cases presented significant increased deposition of collagen, fibronectin, versican, and TGF-β, and decreased decorin density when compared to non-COVID-19 cases of similar MV duration. TGF-β was precociously increased in COVID-19 patients with MV duration up to six days. Lung collagen was higher in women with COVID-19, with a transition of upregulated genes related to fibrillogenesis to collagen production and ECM disassembly along the MV course.

Conclusions

Fatal COVID-19 is associated with an early TGF-β expression lung environment after the MV onset, followed by a disordered ECM assembly. This uncontrolled process resulted in a prominent collagen deposition when compared to other causes of ARDS. Our data provides pathological substrates to better understand the high prevalence of pulmonary abnormalities in patients surviving COVID-19.
Discovery and overproduction of novel highly bioactive pamamycins through transcriptional engineering of the biosynthetic gene cluster
Authors: Eckert Nikolas , Rebets Yuriy , Horbal Lilya , Zapp Josef , Herrmann Jennifer , Busche Tobias , Müller Rolf , Kalinowski Jörn , Luzhetskyy Andriy
Published: November 2023

Background

Pamamycins are a family of highly bioactive macrodiolide polyketides produced by Streptomyces alboniger as a complex mixture of derivatives with molecular weights ranging from 579 to 705 Daltons. The large derivatives are produced as a minor fraction, which has prevented their isolation and thus studies of chemical and biological properties.

Results

Herein, we describe the transcriptional engineering of the pamamycin biosynthetic gene cluster (pam BGC), which resulted in the shift in production profile toward high molecular weight derivatives. The pam BGC library was constructed by inserting randomized promoter sequences in front of key biosynthetic operons. The library was expressed in Streptomyces albus strain with improved resistance to pamamycins to overcome sensitivity-related host limitations. Clones with modified pamamycin profiles were selected and the properties of engineered pam BGC were studied in detail. The production level and composition of the mixture of pamamycins was found to depend on balance in expression of the corresponding biosynthetic genes. This approach enabled the isolation of known pamamycins and the discovery of three novel derivatives with molecular weights of 663 Da and higher. One of them, homopamamycin 677A, is the largest described representative of this family of natural products with an elucidated structure. The new pamamycin 663A shows extraordinary activity (IC50 2 nM) against hepatocyte cancer cells as well as strong activity (in the one-digit micromolar range) against a range of Gram-positive pathogenic bacteria.

Conclusion

By employing transcriptional gene cluster refactoring, we not only enhanced the production of known pamamycins but also discovered novel derivatives exhibiting promising biological activities. This approach has the potential for broader application in various biosynthetic gene clusters, creating a sustainable supply and discovery platform for bioactive natural products.
Role of lipins in cardiovascular diseases
Authors: Ding Zerui , Song Hongyu , Wang Fang
Published: November 2023

Lipin family members in mammals include lipins 1, 2, and 3. Lipin family proteins play a crucial role in lipid metabolism due to their bifunctionality as both transcriptional coregulators and phosphatidate phosphatase (PAP) enzymes. In this review, we discuss the structural features, expression patterns, and pathophysiologic functions of lipins, emphasizing their direct as well as indirect roles in cardiovascular diseases (CVDs). Elucidating the regulation of lipins facilitates a deeper understanding of the roles of lipins in the processes underlying CVDs. The activity of lipins is modulated at various levels, e.g., in the form of the transcription of genes, post-translational modifications, and subcellular protein localization. Because lipin characteristics are undergoing progressive clarification, further research is necessitated to then actuate the investigation of lipins as viable therapeutic targets in CVDs.
Genetically predicted triglycerides mediate the relationship between type 2 diabetes Mellitus and intervertebral disc degeneration
Authors: Chen Ding-Qiang , Xu Wen-Bin , Chen Xin , Xiao Ke-Yi , Que Zhi-Qiang , Sun Nai-Kun , Feng Jin-Yi , Rui Gang
Published: November 2023

Background

To validate the causal relationship between type 2 diabetes mellitus (T2DM) and intervertebral disc degeneration (IVDD) and to identify and quantify the role of triglycerides (TGs) as potential mediators.

Methods

A two-sample Mendelian randomization (MR) analyses of T2DM (61,714 cases and 1178 controls) and IVDD (20,001 cases and 164,682 controls) was performed using genome-wide association studies (GWAS). Moreover, two-step MR was employed to quantify the proportionate impact of TG-mediated T2DM on IVDD.

Results

MR analysis showed that T2DM increased IVDD risk (OR: 1.0466, 95% CI 1.0049–1.0899, P = 0.0278). Reverse MR analyses demonstrated that IVDD does not affect T2DM risk (P = 0.1393). The proportion of T2DM mediated through TG was 11.4% (95% CI 5.5%-17.4%).

Conclusion

This work further validates the causality between T2DM and IVDD, with a part of the effect mediated by TG, but the greatest impacts of T2DM on IVDD remain unknown. Further studies are needed to identify other potential mediators.
Six-month cost-effectiveness of adding motivational interviewing or a stratified vocational advice intervention to usual case management for workers with musculoskeletal disorders: the MI-NAV economic evaluation
Authors: Tingulstad Alexander , Maas Esther T. , Rysstad Tarjei , Øiestad Britt Elin , Aanesen Fiona , Pripp Are Hugo , Van Tulder Maurits W. , Grotle Margreth
Published: November 2023

Objectives

This study evaluates the six-month cost-effectiveness and cost-benefits of motivational interviewing (MI) or a stratified vocational advice intervention (SVAI) added to usual case management (UC) for workers on sick leave due to musculoskeletal disorders.

Methods

This study was conducted alongside a three-arm RCT including 514 employed workers on sick leave for at least 50% for ≥ 7 weeks. All participants received UC. The UC + MI group received two MI sessions, and the UC + SVAI group received 1–4 SVAI sessions. Sickness absence days, quality-adjusted life-years (QALYs), and societal costs were measured between baseline and six months.

Results

Adding MI to UC, resulted in incremental cost-reduction of -2580EUR (95%CI -5687;612), and a reduction in QALYs of -0.001 (95%CI -0.02;0.01). Secondly, adding MI to UC resulted in an incremental cost-reduction of -538EUR (95%CI -1358;352), and reduction of 5.08 (95%CI -3.3;13.5) sickness-absence days. Financial return estimates were positive, but not statistically significant. Adding SVAI to UC, resulted in an incremental cost-reduction of -2899 EUR (95% CI -5840;18), and a reduction in QALYs of 0.002 (95% CI -0.02;0.01). Secondly, adding SVAI to UC resulted in an statistically significant incremental cost-reduction of -695 EUR (95% CI -1459;-3), and a reduction of 7.9 (95% CI -0.04;15.9) sickness absence days. Financial return estimates were positive and statistically significant. The probabilities of cost-effectiveness for QALYs were high for adding MI or SVAI (ceiling ratio 0.90).

Conclusions

In comparison to UC only, adding MI to UC tends to be cost-effective. Adding SVAI to UC is cost-effective for workers on sick leave due to musculoskeletal disorders.

Trial registration

ClinicalTrials.gov (identifier: NCT03871712).
Giant benign intrathoracic schwannoma: a decade-long progression towards fatality
Authors: Miyawaki Michiyo , Karashima Takashi , Abe Miyuki , Takumi Yohei , Hashimoto Takafumi , Kamohara Ryotaro , Osoegawa Atsushi , Sugio Kenji
Published: November 2023

Background

Intrathoracic neurogenic tumors arise from sympathetic nerve trunks and intercostal nerves; more than 90% are benign. Schwannomas are the most common histological variety, but fatalities due to giant schwannomas are rare.

Case presentation

We report a case of a 65-year-old woman who presented with chest pain and cough. Computed tomography (CT) revealed a large left chest wall mass of 130-mm in size, and the patient was referred to our department. Tumor biopsy was performed under local anesthesia, and a diagnosis of schwannoma was made. Ten years previously, a 30-mm tumor had been noted in the left third intercostal space by a previous doctor, but follow-up had been interrupted owing to depressive disorder. Although we planned to perform intercostal artery embolization followed by chest wall tumor resection, the patient did not consent to surgery due to uncontrolled depression. After four months, she developed respiratory failure caused by compression due to an enlarged tumor and died. Autopsy also revealed a benign schwannoma with no malignant findings.

Conclusions

Although schwannomas are benign tumors, there are some very rare cases in which they can become huge and life-threatening. Therefore, a benign tumor should not be neglected, and if surgery is not possible at the time of diagnosis, a regular follow up is necessary, in order not to miss the right timing for surgery.
Intractable chylous leak after radical esophagectomy treated with radiotherapy
Authors: Ahn Seha , Lee Heejin , Kang Joon Kyu , Kim In Sub , Moon Youngkyu , Choi Jung Suk , Won Yoo Dong , Jeong Seong Cheol , Choi Si Young
Published: November 2023

Postoperative chylous leak after esophagectomy is a rare but potentially life-threatening complication that results in hypovolemia, electrolyte imbalance, malnutrition, and immunologic deficiency. However, the management of postoperative chylous leak remains controversial. Following a diagnosis of esophageal cancer, a 64-year-old man was treated by video-assisted thoracoscopic esophagectomy, laparoscopic gastric tube formation, prophylactically thoracic duct ligation, and reconstruction with esophagogastrostomy at the neck level. Massive postoperative drainage from the thorax and abdomen did not initially meet the diagnostic criteria for chylothorax, which was ultimately diagnosed 3 weeks after the operation. Despite various treatments including total parenteral nutrition, octreotide and midodrine, reoperation (thoracic duct ligation and mechanical pleurodesis), and thoracic duct embolization, the chylous leak persisted. Finally, low-dose radiation therapy was administered with a daily dose of 2 Gy and completed at a total dose of 14 Gy. After this, the amount of pleural effusion gradually decreased over 2 weeks, and the last drainage tube was removed. The patient was alive and well at 60 months postoperatively. Herein, we describe a patient with intractable chylous leak after esophagectomy, which persisted despite conservative treatment, thoracic duct ligation, and embolization, but was finally successfully treated with radiotherapy.
Non-drug interventions of traditional Chinese medicine in preventing type 2 diabetes: a review
Authors: Liu Jingying , Yao Chun , Wang Yitao , Zhao Jinmin , Luo Hua
Published: November 2023

Traditional Chinese medicine (TCM) is increasingly used to manage type 2 diabetes and its nonpharmacological interventions are showing potential for preventing type 2 diabetes. This study mainly reviews relevant research. The most mentioned non-drug treatments for preventing type 2 diabetes in TCM are healthy diet, physical activity, emotional therapy, and acupuncture. In most studies, blood glucose status in patients with prediabetes and type 2 diabetes was significantly improved after TCM non-drug interventions, and there was no significant difference between the adverse effect of TCM and control groups or other intervention groups, while the methodological quality of the clinical trials involving TCM generally kept a low level. The effectiveness of TCM in preventing type 2 diabetes has yet to be validated in large randomized controlled trials and the underlying mechanism also needs further exploration.
Optogenetic activation of dopamine D1 receptors in island cells of medial entorhinal cortex inhibits temporal association learning
Authors: Yokose Jun , Yamamoto Naoki , Ogawa Sachie K. , Kitamura Takashi
Published: November 2023

A critical feature of episodic memory formation is to associate temporally segregated events as an episode, called temporal association learning. The medial entorhinal cortical-hippocampal (EC-HPC) networks is essential for temporal association learning. We have previously demonstrated that pyramidal cells in the medial EC (MEC) layer III project to the hippocampal CA1 pyramidal cells and are necessary for trace fear conditioning (TFC), which is an associative learning between tone and aversive shock with the temporal gap. On the other hand, Island cells in MECII, project to GABAergic neurons in hippocampal CA1, suppress the MECIII input into the CA1 pyramidal cells through the feed-forward inhibition, and inhibit TFC. However, it remains unknown about how Island cells activity is regulated during TFC. In this study, we report that dopamine D1 receptor is preferentially expressed in Island cells in the MEC. Optogenetic activation of dopamine D1 receptors in Island cells facilitate the Island cell activity and inhibited hippocampal CA1 pyramidal cell activity during TFC. The optogenetic activation caused the impairment of TFC memory recall without affecting contextual fear memory recall. These results suggest that dopamine D1 receptor in Island cells have a crucial role for the regulation of temporal association learning.
Differential immunomodulatory effects of epirubicin/cyclophosphamide and docetaxel in breast cancer patients
Authors: Wimmer Kerstin , Sachet Monika , Ramos Cristiano , Frantal Sophie , Birnleitner Hanna , Brostjan Christine , Exner Ruth , Filipits Martin , Bago-Horvath Zsuzsanna , Rudas Margaretha , Bartsch Rupert , Gnant Michael , Singer Christian F. , Balic Marija , Egle Daniel , Oehler Rudolf , Fitzal Florian
Published: November 2023

Background

Epirubicin/cyclophosphamide (EC) and docetaxel (D) are commonly used in a sequential regimen in the neoadjuvant treatment of early, high-risk or locally advanced breast cancer (BC). Novel approaches to increase the response rate combine this treatment with immunotherapies such as PD-1 inhibition. However, the expected stimulatory effect on lymphocytes may depend on the chemotherapy backbone. Therefore, we separately compared the immunomodulatory effects of EC and D in the setting of a randomized clinical trial.

Methods

Tumor and blood samples of 154 patients from the ABCSG-34 trial were available (76 patients received four cycles of EC followed by four cycles of D; 78 patients get the reverse treatment sequence). Tumor-infiltrating lymphocytes, circulating lymphocytes and 14 soluble immune mediators were determined at baseline and at drug change. Furthermore, six BC cell lines were treated with E, C or D and co-cultured with immune cells.

Results

Initial treatment with four cycles of EC reduced circulating B and T cells by 94% and 45%, respectively. In contrast, no comparable effects on lymphocytes were observed in patients treated with initial four cycles of D. Most immune mediators decreased under EC whereas D-treatment resulted in elevated levels of CXCL10, urokinase-type plasminogen activator (uPA) and its soluble receptor (suPAR). Accordingly, only the exposure of BC cell lines to D induced similar increases as compared to E. While treatment of BC cells with E was associated with cell shrinkage and apoptosis, D induced cell swelling and accumulation of cells in G2 phase.

Conclusion

The deleterious effect of EC on lymphocytes indicates strong immunosuppressive properties of this combination therapy. D, in contrast, has no effect on lymphocytes, but triggers the secretion of stimulatory proteins in vivo and in vitro, indicating a supportive effect on the immune system. Underlying differences in the induced cell death might be causal. These divergent immunomodulatory effects of epirubicin/cyclophosphamide and docetaxel should be considered when planning future combinations with immunotherapies in breast cancer.