bluuebunny/crossref_metadata_2025_split huggingface dataset:
Teaching evidence-based medicine in Mexico: a systematic review of medical doctor curriculums at a national level
Authors: Rodriguez David , Martinez-Alvarado Jhon Diego , Garcia-Toto Rebeca , Genel-Rey Tania Itzel 
Published: June 2022

ObjectivesTo assess the teaching of evidence-based medicine (EBM) in medical curriculums. As a secondary objective, we assessed the representativeness of science courses related to EBM.Design and settingSystematic review. Accredited curriculums by the Mexican Council for the Accreditation of Medical Education.Main outcome measuresWe provided a descriptive analysis of the required or elective EBM courses and EBM-related courses, academic credits and teaching period. EBM-related courses included research methodology, epidemiology, biostatistics, clinical research, public health, clinical epidemiology, scientific dissemination and health informatics to explore scientific education and training offered by medical schools. Additionally, we examined the curriculum’s structure, location, type of institution, total programme duration and academic credits. Data collection occurred from December 2020 to February 2021.ResultsWe identified 171 registered curriculums, of which we assessed 60 unique programmes (50% public) in our analysis. We identified 16 EBM single courses on the fifth and sixth semesters, of which 12 (20%) were mandatory and 4 were electives (6.7%). The allocated academic credits for EBM courses are minimal, without difference between public or private institutions, representing 0.08% of the total curriculum. Public health, epidemiology, research methodology and biostatistics courses are offered with greater frequency (55% or less) and curricular value (0.6% or less). In some cases, they are taught as combined courses. Clinical research, health informatics and clinical epidemiology are taught less than EBM, while scientific dissemination is nil.ConclusionIn Mexico, EBM teaching is limited to only one of five curriculums with minimal curricular value. A comprehensive curricular review is necessary across programmes to incorporate EBM as a first step to improve medical education and, consequently, public health. We call to action through an online, collaborative platform with several applications to optimise teaching of EBM.Review protocol registrationThe systematic review protocol is excluded from the International Prospective Register of Systematic Reviews since this platform only accepts systematic reviews with health-related outcomes. Review protocol registration:https://osf.io/3xm2q/
Examining infant and child death clustering among families in the cross-sectional and nationally representative Bangladesh Demographic and Health Survey 2017–2018
Authors: Paul Ronak , Srivastava Shobhit , Rashmi Rashmi 
Published: June 2022

ObjectivesWe aim to examine the phenomenon of infant and child death clustering while considering the unobserved heterogeneity (frailty) at the family level.Design, setting, and participantsWe analysed Bangladesh Demographic and Health Survey 2017–2018 data, including the birth history information for 47 828 children born to 18 134 women. We used Gompertz shared frailty model to control the correlation between event times at the mother level and capture the unobserved risks in infant and child deaths.Outcome measuresWe estimated two sets of survival regression models where the failure event is the survival status of the index child during the infancy period, that is, from birth to 11 months, and childhood period, that is, between 12 and 59 months, respectively. All children who died during infancy and childhood were coded as ‘yes’; otherwise, they were coded as ‘no’.ResultsAbout 2% of mothers experienced two or more infant deaths, and cumulatively these mothers account for 20% of all infant deaths in the sample. Children whose previous sibling was not alive at the time of their conception had 1.86 times (95% CI 1.59 to 2.17) more risk of dying as an infant. However, we did not find a statistically significant effect of death scarring on the risk of child mortality among siblings. Statistically significant frailty effect with a variance of 0.33 (95% CI CI 0.17 to 0.65) and 0.54 (95% CI 0.14 to 2.03)] in infancy and childhood, respectively, indicates the clustering of survival risks within families due to unobserved family-level characteristics shared by the siblings.ConclusionThis study suggests that preceding birth interval, mother’s age at first birth and mother’s education are the most critical factors which can help in reducing scaring effect on infant mortality. Additionally, women from poor socioeconomic strata should be focused on as still an infant, and child mortality is concentrated among poor households.
Impact of biological sex and gender-related factors on public engagement in protective health behaviours during the COVID-19 pandemic: cross-sectional analyses from a global survey
Authors: Dev Rubee , Raparelli Valeria , Bacon Simon L , Lavoie Kim L , Pilote Louise , Norris Colleen M 
Published: June 2022

ObjectiveGiven the role of sociocultural gender in shaping human behaviours, the main objective of this study was to examine whether sex and gender-related factors were associated with the public’s adherence to COVID-19-recommended protective health behaviours.DesignThis was a retrospective analysis of the survey that captured data on people’s awareness, attitudes and behaviours as they relate to the COVID-19 policies.SettingData from the International COVID-19 Awareness and Responses Evaluation survey collected between March 2020 and February 2021 from 175 countries.ParticipantsConvenience sample around the world.Main outcome measuresWe examined the role of sex and gender-related factors in relation to non-adherence of protective health behaviours including: (1) hand washing; (2) mask wearing; and (3) physical distancing. Multivariable logistic regression was conducted to determine the factors associated with non-adherence to behaviours.ResultsAmong 48 668 respondents (mean age: 43 years; 71% female), 98.3% adopted hand washing, 68.5% mask wearing and 76.9% physical distancing. Compared with males, females were more likely to adopt hand washing (OR=1.97, 95% CI: 1.71 to 2.28) and maintain physical distancing (OR=1.28, 95% CI: 1.22 to 1.34). However, in multivariable sex-stratified models, females in countries with higher Gender Inequality Indexes (GII) were less likely to report hand washing (adjusted OR (aOR)=0.47, 95% CI: 0.21 to 1.05). Females who reported being employed (aOR=0.22, 95% CI: 0.10 to 0.48) and in countries with low/medium GIIs (aOR=0.18, 95% CI 0.06 to 0.51) were less likely to report mask wearing. Females who reported being employed were less likely to report physical distancing (aOR=0.39, 95% CI: 0.32 to 0.49).ConclusionWhile females showed greater adherence to COVID-19 protective health behaviours, gender-related factors, including employment status and high country-wide gender inequality, were independently associated with non-adherence. These findings may inform public health and vaccination policies in current as well as future pandemics.
Heterogeneous adverse childhood experiences and cognitive function in an elderly Chinese population: a cohort study
Authors: Yuan Manqiong , Qin Fengzhi , Xu Chuanhai , Fang Ya 
Published: June 2022

ObjectiveTo identify the heterogeneity of adverse childhood experiences (ACEs) as well as their association with cognitive function in an elderly Chinese population.DesignA retrospective cohort study.ParticipantsThe data were from the latest wave of the China Health and Retirement Longitudinal Study and a total of 7222 participants aged ≥60 were included.Primary and secondary outcome measuresLatent class analysis was used to identify the classes characterised by 11 types of ACEs. Cognitive function was measured by the Mini-Mental State Examination (MMSE) and cognitive impairment was defined by education-specific threshold MMSE scores. Logistic models were constructed to examine the relationship between ACE classes and cognitive impairment. Several childhood and adulthood confounding factors were considered.ResultsThree ACE latent classes were identified. Of them, 76.09% were in the ‘Low ACEs’ class, 15.43% were in the ‘Household dysfunction’ class and 8.49% were in the ‘Child maltreatment’ class. The people in the ‘Low ACEs’ class seemed to have better childhood family financial situations and higher education levels. The population in the ‘Household dysfunction’ class tended to live in rural areas and have a higher proportion of men, whereas people in the ‘Child maltreatment’ class showed a significantly higher proportion of women and higher levels of chronic diseases. ‘Child maltreatment’ was related to a higher risk of cognitive impairment (OR=1.37, 95% CI: 1.12 to 1.68), while the risk of ‘Household dysfunction’ was not significantly different from that of the ‘Low ACEs’ participants (OR=1.06, 95% CI: 0.90 to 1.26).ConclusionsThe findings supported differences in cognitive function in elderly Chinese people exposed to different types of ACEs.
Patient experience of residents with restricted primary care access during the COVID-19 pandemic
Authors: Aoki Takuya , Fujinuma Yasuki , Matsushima Masato 
Published: June 2022

ObjectivesTo evaluate primary care access for COVID-19 consultation among residents who have a usual source of care (USC) and to examine their associations with patient experience during the pandemic in Japan.DesignNationwide cross-sectional study.SettingJapanese general adult population.Participants1004 adult residents who have a USC.Main outcome measuresPatient experience assessed by the Japanese version of Primary Care Assessment Tool Short Form (JPCAT-SF).ResultsA total of 198 (19.7%) reported restricted primary care access for COVID-19 consultation despite having a USC. After adjustment for possible confounders, restricted primary care access for COVID-19 consultation was negatively associated with the JPCAT-SF total score (adjusted mean difference = −8.61, 95% CI −11.11 to −6.10). In addition, restricted primary care access was significantly associated with a decrease in all JPCAT-SF domain scores.ConclusionsApproximately one-fifth of adult residents who had a USC reported restricted primary care access for COVID-19 consultation during the pandemic in Japan. Our study also found that restricted primary care access for COVID-19 consultation was negatively associated with a wide range of patient experience including first contact. Material, financial and educational support to primary care facilities, the spread of telemedicine and the application of a patient registration system might be necessary to improve access to primary care during a pandemic.
Single-cell RNA-seq analysis reveals BHLHE40-driven pro-tumour neutrophils with hyperactivated glycolysis in pancreatic tumour microenvironment
Authors: Wang Liwen , Liu Yihao , Dai Yuting , Tang Xiaomei , Yin Tong , Wang Chaofu , Wang Ting , Dong Lei , Shi Minmin , Qin Jiejie , Xue Meilin , Cao Yizhi , Liu Jia , Liu Pengyi , Huang Jinyan , Wen Chenlei , Zhang Jun , Xu Zhiwei , Bai Fan , Deng Xiaxing , Peng Chenghong , Chen Hao , Jiang Lingxi , Chen Saijuan , Shen Baiyong 
Published: June 2022

ObjectiveInnate immunity plays important roles in pancreatic ductal adenocarcinoma (PDAC), as non-T-cell-enriched tumour. Neutrophils are major players in innate immune system. Here, we aimed to explore the heterogeneity and pro-tumour mechanisms of neutrophils in PDAC.DesignWe analysed single-cell transcriptomes of peripheral blood polymorphonuclear leucocytes (PMNs) and tumour-infiltrating immune cells from five patients with PDAC, and performed immunofluorescence/immunohistochemistry staining, multi-omics analysis andin vitroexperiments to validate the discoveries of bioinformatics analysis.ResultsExploration of the heterogeneity of tumour-associated neutrophils (TANs) revealed a terminally differentiated pro-tumour subpopulation (TAN-1) associated with poor prognosis, an inflammatory subpopulation (TAN-2), a population of transitional stage that have just migrated to tumour microenvironment (TAN-3) and a subpopulation preferentially expressing interferon-stimulated genes (TAN-4). Glycolysis signature was upregulated along neutrophil transition trajectory, and TAN-1 was featured with hyperactivated glycolytic activity. The glycolytic switch of TANs was validated by integrative multi-omics approach of transcriptomics, proteomics and metabolomics analysis. Activation of glycolytic activity by LDHA overexpression induced immunosuppression and pro-tumour functions in neutrophil-like differentiated HL-60 (dHL-60) cells. Mechanistic studies revealed BHLHE40, downstream to hypoxia and endoplasmic reticulum stress, was a key regulator in polarisation of neutrophils towards TAN-1 phenotype, and direct transcriptional regulation of BHLHE40 on TAN-1 marker genes was demonstrated by chromatin immunoprecipitation assay. Pro-tumour and immunosuppression functions were observed in dHL-60 cells overexpressing BHLHE40. Importantly, immunohistochemistry analysis of PDAC tissues revealed the unfavourable prognostic value of BHLHE40+neutrophils.ConclusionThe dynamic properties of TANs revealed by this study will be helpful in advancing PDAC therapy targeting innate immunity.
DuoBody-CD40x4-1BB induces dendritic-cell maturation and enhances T-cell activation through conditional CD40 and 4-1BB agonist activity
Authors: Muik Alexander , Adams Homer C , Gieseke Friederike , Altintas Isil , Schoedel Kristina B , Blum Jordan M , Sänger Bianca , Burm Saskia M , Stanganello Eliana , Verzijl Dennis , Spires Vanessa M , Vascotto Fulvia , Toker Aras , Quinkhardt Juliane , Fereshteh Mark , Diken Mustafa , Satijn David P E , Kreiter Sebastian , Ahmadi Tahamtan , Breij Esther C W , Türeci Özlem , Sasser Kate , Sahin Ugur , Jure-Kunkel Maria 
Published: June 2022

BackgroundDespite the preclinical promise of CD40 and 4-1BB as immuno-oncology targets, clinical efforts evaluating CD40 and 4-1BB agonists as monotherapy have found limited success. DuoBody-CD40×4-1BB (GEN1042/BNT312) is a novel investigational Fc-inert bispecific antibody for dual targeting and conditional stimulation of CD40 and 4-1BB to enhance priming and reactivation of tumor-specific immunity in patients with cancer.MethodsCharacterization of DuoBody-CD40×4-1BB in vitro was performed in a broad range of functional immune cell assays, including cell-based reporter assays, T-cell proliferation assays, mixed-lymphocyte reactions and tumor-infiltrating lymphocyte assays, as well as live-cell imaging. The in vivo activity of DuoBody-CD40×4-1BB was assessed in blood samples from patients with advanced solid tumors that were treated with DuoBody-CD40×4-1BB in the dose-escalation phase of the first-in-human clinical trial (NCT04083599).ResultsDuoBody-CD40×4-1BB exhibited conditional CD40 and 4-1BB agonist activity that was strictly dependent on crosslinking of both targets. Thereby, DuoBody-CD40×4-1BB strengthened the dendritic cell (DC)/T-cell immunological synapse, induced DC maturation, enhanced T-cell proliferation and effector functions in vitro and enhanced expansion of patient-derived tumor-infiltrating lymphocytes ex vivo. The addition of PD-1 blocking antibodies resulted in potentiation of T-cell activation and effector functions in vitro compared with either monotherapy, providing combination rationale. Furthermore, in a first-in-human clinical trial, DuoBody-CD40×4-1BB mediated clear immune modulation of peripheral antigen presenting cells and T cells in patients with advanced solid tumors.ConclusionDuoBody-CD40×4-1BB is capable of enhancing antitumor immunity by modulating DC and T-cell functions and shows biological activity in patients with advanced solid tumors. These findings demonstrate that targeting of these two pathways with an Fc-inert bispecific antibody may be an efficacious approach to (re)activate tumor-specific immunity and support the clinical investigation of DuoBody-CD40×4-1BB for the treatment of cancer.
Peripheral blood immune cell dynamics reflect antitumor immune responses and predict clinical response to immunotherapy
Authors: Hwang Michael , Canzoniero Jenna Vanliere , Rosner Samuel , Zhang Guangfan , White James R , Belcaid Zineb , Cherry Christopher , Balan Archana , Pereira Gavin , Curry Alexandria , Niknafs Noushin , Zhang Jiajia , Smith Kellie N , Sivapalan Lavanya , Chaft Jamie E , Reuss Joshua E , Marrone Kristen , Murray Joseph C , Li Qing Kay , Lam Vincent , Levy Benjamin P , Hann Christine , Velculescu Victor E , Brahmer Julie R , Forde Patrick M , Seiwert Tanguy , Anagnostou Valsamo 
Published: June 2022

BackgroundDespite treatment advancements with immunotherapy, our understanding of response relies on tissue-based, static tumor features such as tumor mutation burden (TMB) and programmed death-ligand 1 (PD-L1) expression. These approaches are limited in capturing the plasticity of tumor–immune system interactions under selective pressure of immune checkpoint blockade and predicting therapeutic response and long-term outcomes. Here, we investigate the relationship between serial assessment of peripheral blood cell counts and tumor burden dynamics in the context of an evolving tumor ecosystem during immune checkpoint blockade.MethodsUsing machine learning, we integrated dynamics in peripheral blood immune cell subsets, including neutrophil-lymphocyte ratio (NLR), from 239 patients with metastatic non-small cell lung cancer (NSCLC) and predicted clinical outcome with immune checkpoint blockade. We then sought to interpret NLR dynamics in the context of transcriptomic and T cell repertoire trajectories for 26 patients with early stage NSCLC who received neoadjuvant immune checkpoint blockade. We further determined the relationship between NLR dynamics, pathologic response and circulating tumor DNA (ctDNA) clearance.ResultsIntegrated dynamics of peripheral blood cell counts, predominantly NLR dynamics and changes in eosinophil levels, predicted clinical outcome, outperforming both TMB and PD-L1 expression. As early changes in NLR were a key predictor of response, we linked NLR dynamics with serial RNA sequencing deconvolution and T cell receptor sequencing to investigate differential tumor microenvironment reshaping during therapy for patients with reduction in peripheral NLR. Reductions in NLR were associated with induction of interferon-γ responses driving the expression of antigen presentation and proinflammatory gene sets coupled with reshaping of the intratumoral T cell repertoire. In addition, NLR dynamics reflected tumor regression assessed by pathological responses and complemented ctDNA kinetics in predicting long-term outcome. Elevated peripheral eosinophil levels during immune checkpoint blockade were correlated with therapeutic response in both metastatic and early stage cohorts.ConclusionsOur findings suggest that early dynamics in peripheral blood immune cell subsets reflect changes in the tumor microenvironment and capture antitumor immune responses, ultimately reflecting clinical outcomes with immune checkpoint blockade.
Oncolytic virus expressing PD-1 inhibitors activates a collaborative intratumoral immune response to control tumor and synergizes with CTLA-4 or TIM-3 blockade
Authors: Ju Fei , Luo Yong , Lin Chaolong , Jia Xian , Xu Zilong , Tian Rui , Lin Yanhua , Zhao Min , Chang Yating , Huang Xiaoxuan , Li Shaopeng , Ren Wenfeng , Qin Yaning , Yu Mengqin , Jia Jizong , Han Jinle , Luo Wenxin , Zhang Jun , Fu Guo , Ye Xiangzhong , Huang Chenghao , Xia Ningshao 
Published: June 2022

BackgroundOncolytic viruses (OVs) are capable to inflame the tumor microenvironment (TME) and elicit infiltrating tumor-specific T cell responses. However, OV treatment negatively alters the cancer-immune set point in tumors to attenuate the antitumor immune response, which suggests the necessity of dissecting the immune landscape of the virus-treated tumors and developing novel strategies to maximize the potential of OVs. The aim of this study is to investigate the effect of the single-chain variable fragment (scFv)-armed OVs targeting PD-1 on the TME, and ultimately overcome localized immunosuppression to sensitize tumors to immunotherapies.MethodsA tumor-selective oncolytic herpes simplex virus vector was engineered to encode a humanized scFv against human PD-1 (hPD-1scFv) (YST-OVH). The antitumor efficacy of YST-OVH was explored in multiple therapeutic mouse models. The neurotoxicity and safety of YST-OVH were evaluated in nonhuman primates. The precise dynamics in the TME involved in YST-OVH treatment were dissected using cytometry by time-of-flight (CyTOF).ResultsThe identified hPD-1scFv showed superior T-cell activating activity. Localized delivery of hPD-1scFv by YST-OVH promotes systemic antitumor immunity in humanized PD-1 mouse models of established cancer. Immune profiling of tumors using CyTOF revealed the enhanced antitumor effect of YST-OVH, which largely relied on CD8+T cell activity by augmenting the tumor infiltration of effector CD8+T cells and establishment of memory CD8+T cells and reducing associated CD8+T cell exhaustion. Furthermore, YST-OVH treatment modified the cancer-immune set point of tumors coupled to coexpression of CTLA-4 and TIM-3 on exhausted CD8+T cells and high levels of CTLA-4+Treg cells. A combination approach incorporating anti-CTLA-4 or anti-TIM-3 further improved efficacy by increasing tumor immunogenicity and activating antitumor adaptive immune responses. Moreover, this therapeutic strategy showed no neurotoxicity and was well tolerated in nonhuman primates. The benefit of intratumoral hPD-1scFv expression was also observed in humanized mice bearing human cancer cells.ConclusionLocalized delivery of PD-1 inhibitors by engineered YST-OVH was a highly effective and safe strategy for cancer immunotherapy. YST-OVH also synergized with CTLA-4 or TIM-3 blockade to enhance the immune response to cancer. These data provide a strong rationale for further clinical evaluation of this novel therapeutic approach.
Time to first treatment and risk of disability pension in relapsing-remitting multiple sclerosis
Authors: Wandall-Holm Malthe Faurschou , Buron Mathias Due , Kopp Tine Iskov , Thielen Karsten , Sellebjerg Finn , Magyari Melinda 
Published: June 2022

BackgroundInitiation of disease-modifying therapy early in the disease course of relapsing-remitting multiple sclerosis (RRMS) has demonstrated beneficial effects on clinical outcomes, but socioeconomic outcomes remain largely unexplored.ObjectiveTo investigate the association between the delay from disease onset to first treatment and the hazard of disability pension.MethodsWe performed a population-based cohort study with data from the nationwide Danish Multiple Sclerosis Registry and Danish nationwide registries. Patients with a disease onset between 1 January 1996 to 5 April 2016 were followed until disability pension or a competing risk/censoring event. 7859 patients were assessed for eligibility of which 5208 were included in the final cohort. Key inclusion criteria were: a diagnosis of multiple sclerosis, relapsing-remitting phenotype, treatment in history, age 18–65 years and an Expanded Disability Status Scale≤4. Patients were categorised according to time from onset to first treatment: within 1 year (early), between 1 and 4 years (intermediate) and from 4 to 8 years (late).ResultsOf the 5208 patients, 1922 were early, 2126 were intermediate and 1160 were late. Baseline clinical and socioeconomic variables were well balanced. The hazard of receiving disability pension increased with increasing delay of treatment initiation compared with the early group. Cox regression estimates adjusted for clinical and socioeconomic confounders: intermediate (HR, 1.37; 95% CI, 1.12 to 1.68) and late (HR, 1.97; 95% CI, 1.55 to 2.51).ConclusionEarly treatment initiation is associated with a reduced risk of disability pension in patients with RRMS. This finding underlines the importance of early diagnosis and treatment on a patient-centred, socioeconomic disability milestone.