bluuebunny/crossref_metadata_2025_split huggingface dataset:
An apicomplexan bromodomain protein, TgBDP1, associates with diverse epigenetic factors to regulate essential transcriptional processes in
Toxoplasma gondii
Authors: Fleck Krista , McNutt Seth , Chu Feixia , Jeffers Victoria 
Published: June 2023

ABSTRACT

The protozoan pathogen
Toxoplasma gondii
relies on tight regulation of gene expression to invade and establish infection in its host. The divergent gene regulatory mechanisms of
Toxoplasma
and related apicomplexan pathogens rely heavily on regulators of chromatin structure and histone modifications. The important contribution of histone acetylation for
Toxoplasma
in both acute and chronic infection has been demonstrated, where histone acetylation increases at active gene loci. However, the direct consequences of specific histone acetylation marks and the chromatin pathway that influences transcriptional regulation in response to the modification are unclear. As a reader of lysine acetylation, the bromodomain serves as a mediator between the acetylated histone and transcriptional regulators. Here we show that the bromodomain protein, TgBDP1, which is conserved among Apicomplexa and within the Alveolata superphylum, is essential for
Toxoplasma
asexual proliferation. Using cleavage under targets and tagmentation, we demonstrate that TgBDP1 is recruited to transcriptional start sites of a large proportion of parasite genes. Transcriptional profiling during TgBDP1 knockdown revealed that loss of TgBDP1 leads to major dysregulation of gene expression, implying multiple roles for TgBDP1 in both gene activation and repression. This is supported by interactome analysis of TgBDP1 demonstrating that TgBDP1 forms a core complex with two other bromodomain proteins and an ApiAP2 factor. This core complex appears to interact with other epigenetic factors such as nucleosome remodeling complexes. We conclude that TgBDP1 interacts with diverse epigenetic regulators to exert opposing influences on gene expression in the
Toxoplasma
tachyzoite.

IMPORTANCE

Histone acetylation is critical for proper regulation of gene expression in the single-celled eukaryotic pathogen
Toxoplasma gondii
. Bromodomain proteins are “readers” of histone acetylation and may link the modified chromatin to transcription factors. Here, we show that the bromodomain protein TgBDP1 is essential for parasite survival and that loss of TgBDP1 results in global dysregulation of gene expression. TgBDP1 is recruited to the promoter region of a large proportion of parasite genes, forms a core complex with two other bromodomain proteins, and interacts with different transcriptional regulatory complexes. We conclude that TgBDP1 is a key factor for sensing specific histone modifications to influence multiple facets of transcriptional regulation in
Toxoplasma gondii
.
Associations between modest reductions in kidney function and adverse outcomes in young adults: retrospective, population based cohort study
Authors: Hussain Junayd , Grubic Nicholas , Akbari Ayub , Canney Mark , Elliott Meghan J , Ravani Pietro , Tanuseputro Peter , Clark Edward G , Hundemer Gregory L , Ramsay Tim , Tangri Navdeep , Knoll Greg A , Sood Manish M 
Published: June 2023

Abstract

Objective
To study age specific associations of modest reductions in estimated glomerular filtration rate (eGFR) with adverse outcomes.

Design
Retrospective, population based cohort study.

Setting
Linked healthcare administrative datasets in Ontario, Canada.

Participants

Adult residents (18-65 years) with at least one outpatient eGFR value (categorized in 10 unit increments from 50 mL/min/1.73m
2
to >120 mL/min/1.73m
2
), with no history of kidney disease.

Main outcome measures

eGFRs and hazard ratios of composite adverse outcome (all cause mortality, any cardiovascular event, and kidney failure) stratified by age (18-39 years, 40-49 years, and 50-65 years), and relative to age specific eGFR referents (100-110 mL/min/1.73m
2
) for ages 18-39 years, 90-100 for 40-49 years, 80-90 for 50-65 years).

Results

From 1 January 2008 to 31 March 2021, among 8 703 871 adults (mean age 41.3 (standard deviation 13.6) years; mean index eGFR 104.2 mL/min/1.73m
2
(standard deviation 16.1); median follow-up 9.2 years (interquartile range 5.7-11.4)), modestly reduced eGFR measurements specific to age were recorded in 18.0% of those aged 18-39, 18.8% in those aged 40-49, and 17.0% in those aged 50-65. In comparison with age specific referents, adverse outcomes were consistently higher by hazard ratio and incidence for ages 18-39 compared with older groups across all eGFR categories. For modest reductions (eGFR 70-80 mL/min/1.73m
2
), the hazard ratio for ages 18-39 years was 1.42 (95% confidence interval 1.35 to 1.49), 4.39 per 1000 person years; for ages 40-49 years was 1.13 (1.10 to 1.16), 9.61 per 1000 person years; and for ages 50-65 years was 1.08 (1.07 to 1.09), 23.4 per 1000 person years. Results persisted for each individual outcome and in many sensitivity analyses.

Conclusions

Modest eGFR reductions were consistently associated with higher rates of adverse outcomes. Higher relative hazards were most prominent and occurred as early as eGFR <80 mL/min/1.73m
2
in younger adults, compared with older groups. These findings suggest a role for more frequent monitoring of kidney function in younger adults to identify individuals at risk to prevent chronic kidney disease and its complications.
Subsidised housing and diabetes mortality: a retrospective cohort study of 10 million low-income adults in Brazil
Authors: Flores-Ortiz Renzo , Fiaccone Rosemeire L , Leyland Alastair , Millett Christopher , Hone Thomas , Schmidt Maria Inês , Ferreira Andrêa J F , Ichihara Maria Y , Teixeira Camila , Sanchez Mauro N , Pescarini Julia , Aquino Estela M L , Malta Deborah C , Velasquez-Melendez Gustavo , de Oliveira Juliane Fonseca , Craig Peter , Ribeiro-Silva Rita C , Barreto Mauricio L , Katikireddi Srinivasa Vittal 
Published: June 2023

IntroductionHousing-related factors can be predictors of health, including of diabetes outcomes. We analysed the association between subsidised housing residency and diabetes mortality among a large cohort of low-income adults in Brazil.Research design and methodsA cohort of 9 961 271 low-income adults, observed from January 2010 to December 2015, was created from Brazilian administrative records of social programmes and death certificates. We analysed the association between subsidised housing residency and time to diabetes mortality using a Cox model with inverse probability of treatment weighting and regression adjustment. We assessed inequalities in this association by groups of municipality Human Development Index. Diabetes mortality included diabetes both as the underlying or a contributory cause of death.ResultsAt baseline, the mean age of the cohort was 40.3 years (SD 15.6 years), with a majority of women (58.4%). During 29 238 920 person-years of follow-up, there were 18 775 deaths with diabetes as the underlying or a contributory cause. 340 683 participants (3.4% of the cohort) received subsidised housing. Subsidised housing residents had a higher hazard of diabetes mortality compared with non-residents (HR 1.17; 95% CI 1.05 to 1.31). The magnitude of this association was more pronounced among participants living in municipalities with lower Human Development Index (HR 1.30; 95% CI 1.04 to 1.62).ConclusionsSubsidised housing residents had a greater risk of diabetes mortality, particularly those living in low socioeconomic status municipalities. This finding suggests the need to intensify diabetes prevention and control actions and prompt treatment of the diabetes complications among subsidised housing residents, particularly among those living in low socioeconomic status municipalities.
‘You have to use everything and come to some equilibrium’: a qualitative study on hypoglycemia self-management in users of continuous glucose monitor with diverse hypoglycemia experiences
Authors: Lin Yu Kuei , Agni Annika , Chuisano Samantha , de Zoysa Nicole , Fetters Michael , Amiel Stephanie A , Pop-Busui Rodica , DeJonckheere Melissa 
Published: June 2023

IntroductionAlthough continuous glucose monitoring systems (CGMs) can help reduce hypoglycemia, about one-quarter of people with type 1 diabetes (T1D) who use CGMs still either spend at least 1% of the time with dangerously low blood glucose or develop severe hypoglycemia. This study explored experiences around hypoglycemia self-management in people who are living with T1D and using CGMs to identify factors contributing to hypoglycemia development.Research design and methodsPurposive sampling and semistructured interviews with 28 respondents with T1D and using CGMs were conducted to explore experiences around hypoglycemic episodes and hypoglycemia self-management during CGM use. Open coding and thematic analysis were employed to identify emergent themes related to hypoglycemia experiences.ResultsAbout one-third of respondents each respectively spent 0%, 0.1%–0.9% and ≥1% of time in level 2 hypoglycemia; 39% had impaired awareness of hypoglycemia and 32% had severe hypoglycemia in the past 6 months. Four themes were generated: (1) prioritizing symptoms over CGM data (subthemes: hypoglycemia symptoms for confirming hypoglycemia and prompting management actions; minimal management actions without hypoglycemia symptoms); (2) distraction from the demands of daily life; (3) concerns about hypoglycemia management choices (subthemes: fear of rebound hyperglycemia; other health consequences related to sugary food consumption; aversions to treatment foods and treatment food consumption); and (4) social influences on management choices (subthemes: positively perceived social support and inclusion; unwanted attention to oneself or concerns about inconveniencing others; social stigma and criticism related to hypoglycemia and CGM use).ConclusionsDespite using CGMs, people with T1D can face a complex biopsychosocial process of managing hypoglycemia. Interventions for addressing psychosocial and behavioral barriers are needed to improve hypoglycemia self-management in those who continue to face challenges in minimizing hypoglycemia while using CGMs.
Implementation of point-of-care testing and prevalence of cryptococcal antigenaemia among patients with advanced HIV disease in Mumbai, India
Authors: Acharya Shrikala , Allam Ramesh Reddy , Karanjkar Vijay Kumar , Rathod Dhirubhai , Mahajan Raman , Deshpande Prashant , Palkar Amol , Todmal Shashikant , Koli Sagar , Dhande Sachin , Dale Jayesh , Yeldandi Vijay V , Harshana Amit , Agarwal Reshu , Upadhyaya Sunita , Nyendak Melissa 
Published: June 2023

ObjectivesTo describe the implementation of screening for cryptococcal antigenaemia by point-of-care (POC) serum cryptococcal antigen (CrAg) lateral flow assay, measure the prevalence and factors associated with serum cryptococcal antigenaemia in the routine programmatic setting.DesignCross-sectional study.SettingSeventeen publicly funded antiretroviral therapy (ART) centres in Mumbai, India.ParticipantsSerum CrAg screening was offered to all adolescents (>10 years of age) and adults with advanced HIV disease (AHD) (CD4 <200 cells/mm3or with WHO clinical stage III/IV) regardless of symptoms of cryptococcal meningitis.Primary and secondary outcome measuresThe primary outcome was to describe the implementation of serum CrAg screening and secondary outcome was to measure the prevalence of serum cryptococcal antigenaemia and its risk factors.ResultsA total of 2715 patients with AHD were tested for serum CrAg by POC assay. Of these, 25 (0.9%) had a CrAg positive result. Among CrAg-positive patients, only one had symptoms. Serum CrAg positivity was 3.6% (6/169) and 1.6% (6/520) among those presenting with CD4 <100 cells/mm3in the treatment naïve and treatment experienced group, respectively. On multivariable analysis, CD4 count <100 cells/mm3(OR: 2.3, 95% CI 1.01 to 5.3; p=0.05) and people living with HIV who were treatment naïve (OR: 2.5, 95% CI 1.04 to 6.0; p=0.04) were significantly associated with a positive serum CrAg result. Lumbar puncture was obtained in 20/25 patients within 4 days (range: 1–4 days) of positive serum CrAg result and one person was confirmed to have meningitis. All serum CrAg-positive patients who had a negative cerebrospinal fluid CrAg were offered pre-emptive therapy.ConclusionsImplementation of a POC CrAg assay was possible with existing ART centre staff. Initiation of pre-emptive therapy and management of cryptococcal antigenaemia are operationally feasible at ART centres. The Indian National AIDS Control Programme may consider reflexive CrAg screening of all AHD patients with CD4 <100 cells/mm3.
Feasibility study and determination of prerequisites of telecare programme to enhance patient management in lung transplantation: a qualitative study from the perspective of Iranian healthcare providers
Authors: Gholamzadeh Marsa , Safdari Reza , Amini Shahideh , Abtahi Hamidreza 
Published: June 2023

BackgroundNon-adherence to treatment plans, follow-up visits and healthcare advice is a common obstacle in the management of lung transplant patients. This study aims to investigate experts’ views on the needs and main aspects of telecare programmes for lung transplantation.DesignA qualitative study incorporating an inductive thematic analysis.SettingLung transplant clinic and thoracic research centre.ParticipantsClinicians: four pulmonologists, two cardiothoracic surgeons, two general physicians, two pharmacotherapists, one cardiologist, one nurse and one medical informatician.MethodThis study adopted a focus group discussion technique to gather experts’ opinions on the prerequisites and features of a telecare programme in lung transplantation. All interviews were coded and combined into main categories and themes. Thematic analysis was performed to extract the key concepts using ATLAS.Ti. Ultimately, all extracted themes were integrated to devise a conceptual model.ResultsTen focus groups with 13 participants were conducted. Forty-six themes and subthemes were extracted through the thematic analysis. The main features of the final programme were extracted from expert opinions through thematic analysis, such as continuous monitoring of symptoms, drug management, providing a specific care plan for each patient, educating patients module, creating an electronic medical record to collect patient information, equipping the system with decision support tools, smart electronic prescription and the ability to send messages to the care team. The prerequisites of the system were summarised in self-care activities, clinician’s tasks and required technologies. In addition, the barriers and benefits of using a telecare system to enhance the quality of care were determined.ConclusionOur investigation recognised the main factors that must be considered to design a telecare programme to provide ideal continuous care for lung transplant patients. Users should further explore the proposed model to support the development of telecare interventions at the point of care.
Sex differences in sledging injuries: a retrospective 10-season study from a Swiss level 1 trauma centre
Authors: Klukowska-Rötzler Jolanta , Buerzle Annika , Exadaktylos Aristomenis Konstantinos , Niemann Steffen , Bürgi Flavia , Jakob Dominik Andreas 
Published: June 2023

ObjectivesSledging is a popular and traditional winter sport in Switzerland. This study examines injury patterns of patients who presented to a tertiary trauma centre in Switzerland following sledging trauma, focusing on sex differences.MethodsRetrospective single-centre study over 10 winters (2012–2022), including all patients experiencing sledging-related trauma. Injury history was collected and analysed from the patient data and demographic information. The Abbreviated Injury Scale and the Injury Severity Score (ISS) were used to classify injury types and severity.Results193 patients were identified with sledging injuries. The median age was 46 (IQR 28–65), and 56% were female. The most frequent mechanism of injury was a fall (70%), followed by collision (27%) and other fall on slopes (6%). Lower extremities (36%), trunk (20%) and head/neck (15%) were the most frequently injured body areas. Fourteen per cent of patients were admitted with head injuries, whereas females were significantly more likely to present with head injuries than males (p=0.047). Males were significantly more often admitted with fractures to the upper extremities than females (p=0.049). The median ISS was 4 (IQR 1–5), without significant differences between males and females (p=0.290). The hospital admission rate was 28.5% for sledging-related injuries. The median length of stay for patients admitted to the hospital was 5 (IQR 4–8) days. The total cost for all patients was CHF1 292 501, with a median of CHF1009 per patient (IQR CHF458–CHF5923).ConclusionSledging injuries are common and may result in serious injuries. The lower extremities, trunk and head/neck are frequently injured and could be specifically protected with safety devices. Multiple injuries were statistically more frequent in women compared with men. Males were significantly more often admitted with fractures to the upper extremities, and females were more likely to sustain head injuries. The findings can help to develop data-driven measures to prevent sledging accidents in Switzerland.
Systematic review of preoperative n-3 fatty acids in major gastrointestinal surgery
Authors: George Jason , White Daniel , Fielding Barbara , Scott Michael , Rockall Timothy , Whyte Martin Brunel 
Published: June 2023

ObjectivesPerioperative nutrition aims to replenish nutritional stores before surgery and reduce postoperative complications. ‘Immunonutrition’ (including omega-3 fatty acids) may modulate the immune system and attenuate the postoperative inflammatory response. Hitherto, immunonutrition has overwhelmingly been administered in the postoperative period—however, this may be too late to provide benefit.DesignA systematic literature search using MEDLINE and EMBASE for randomized controlled trials (RCTs).SettingPerioperative major gastrointestinal surgery.ParticipantsPatients undergoing major gastrointestinal surgery.InterventionsOmega-3 fatty acid supplementation commenced in the preoperative period, with or without continuation into postoperative period.Main outcome measuresThe effect of preoperative omega-3 fatty acids on inflammatory response and clinical outcomes.Results833 studies were identified. After applying inclusion and exclusion criteria, 12 RCTs, involving 1456 randomized patients, were included. Ten articles exclusively enrolled patients with cancer. Seven studies used a combination of EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) as the intervention and five studies used EPA alone. Eight out of 12 studies continued preoperative nutritional support into the postoperative period.Of the nine studies reporting mortality, no difference was seen. Duration of hospitalisation ranged from 4.5 to 18 days with intervention and 3.5 to 23.5 days with control. Omega-3 fatty acids had no effect on postoperative C-reactive protein and the effect on cytokines (including tumor necrosis factor-α, interleukin (IL)-6 and IL-10) was inconsistent. Ten of the 12 studies had low risk of bias, with one study having moderate bias from allocation and blinding.ConclusionsThere is insufficient evidence to support routine preoperative omega-3 fatty acid supplementation for major gastrointestinal surgery, even when this is continued after surgery.PROSPERO registration numberCRD42018108333.
Organ-specific heterogeneity in tumor-infiltrating immune cells and cancer antigen expression in primary and autologous metastatic lung adenocarcinoma
Authors: Restle David , Dux Joseph , Li Xiaoyu , Byun Alexander J , Choe Jennie K , Li Yan , Vaghjiani Raj G , Thomas Carlos , Misawa Kyohei , Tan Kay See , Jones David R , Chintala Navin K , Adusumilli Prasad S 
Published: June 2023

BackgroundTumor immune microenvironment (TIME) and cancer antigen expression, key factors for the development of immunotherapies, are usually based on the data from primary tumors due to availability of tissue for analysis; data from metastatic sites and their concordance with primary tumor are lacking. Although of the same origin from primary tumor, organ-specific differences in the TIME in metastases may contribute to discordant responses to immune checkpoint inhibitor agents. In immunologically ‘cold’ tumors, cancer antigen-targeted chimeric antigen receptor (CAR) T-cell therapy can promote tumor-infiltrating lymphocytes; however, data on distribution and intensity of cancer antigen expression in primary tumor and matched metastases are unavailable.MethodsWe performed a retrospective review of a prospectively maintained database of patients who had undergone curative resection of pathological stage I–III primary lung adenocarcinoma from January 1995 to December 2012 followed by metastatic recurrence and resection of metastatic tumor (n=87). We investigated the relationship between the primary tumor and metastasis TIME (ie, tumor-infiltrating lymphocytes, tumor-associated macrophages, and programmed death-ligand 1 (PD-L1)) and cancer antigen expression (ie, mesothelin, CA125, and CEACAM6) using multiplex immunofluorescence.ResultsBrain metastases (n=36) were observed to have fewer tumor-infiltrating lymphocytes and greater PD-L1-negative tumor-associated macrophages compared with the primary tumor (p<0.0001); this relatively inhibitory TIME was not observed in other metastatic sites. In one in three patients, expression of PD-L1 is discordant between primary and metastases. Effector-to-suppressor (E:S) cell ratio, median effector cells (CD20+ and CD3+) to suppressor cells (CD68/CD163+) ratio, in metastases was not significantly different between patients with varying E:S ratios in primary tumors. Cancer antigen distribution was comparable between primary and metastases; among patients with mesothelin, cancer antigen 125, or carcinoembryonic antigen adhesion molecule 6 expression in the primary tumor, the majority (51%–75%) had antigen expression in the metastases; however, antigen-expression intensity was heterogenous.ConclusionsIn patients with lung adenocarcinoma, brain metastases, but not other sites of metastases, exhibited a relatively immune-suppressive TIME; this should be considered in the context of differential response to immunotherapy in brain metastases. Among patients with cancer antigen expression in the primary tumor, the majority had antigen expression in metastases; these data can inform the selection of antigen-targeted CARs to treat patients with metastatic lung adenocarcinoma.