bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy of irinotecan, oxaliplatin, and capecitabine (XELOXIRI) regimen with or without targeted drugs in patients with metastatic colorectal cancer: a retrospective cohort study
Authors: Liu Xiu , Ou Kai , Ma Xiaoting , Gao Lizhen , Wang Qi , Zhang Haizeng , Yang Lin
Published: July 2022

Background

Five-fluorouracil, folinic acid, oxaliplatin and irinotecan (FOLFOXIRI) regimen is used as the first-line treatment for metastatic colorectal cancer (mCRC). The use of capecitabine, an oral fluoropyrimidine pro-drug, is feasible and safe; hence, it provides an interesting alternative to 5-fluorouracil in the abovementioned regimen. This study aimed to evaluate the efficacy and safety of capecitabine, oxaliplatin, and irinotecan (XELOXIRI) regimen use with or without targeted drugs in Chinese patients with mCRC.

Methods

We conducted a retrospective, longitudinal cohort study of patients with mCRC who received XELOXIRI regimen with or without targeted drugs (bevacizumab or cetuximab) every 2 weeks between January 2017 and November 2019 at the National Cancer Center/Cancer Hospital, the Chinese Academy of Medical Sciences, and Peking Union Medical College. Treatment efficacy was assessed by investigators by evaluating the objective response rate (ORR) and disease control rate (DCR). Overall survival (OS) was assessed using Cox proportional hazards models. The adverse events were also analyzed.

Results

Sixty-one consecutive patients were examined and followed up for survival. As of November 8, 2021, the median follow-up time was 35.4 months. Disease progression and death occurred in 50 (82%) and 38 (62%) patients, respectively. The median treatment duration of XELOXIRI with or without bevacizumab or cetuximab was 10 cycles (range, 1–12 cycles). The median OS and PFS were 32.2 months (95%CI [24.8–39.6]) and 9.3 months (95% CI [8.1–10.5]), respectively. The ORR of 48 patients with measurable lesions was 70.8%, and the DCR was 89.6%. RAS/BRAF wild-type (HR 0.39; 95% CI [0.16–0.96], p = 0.04) and metastatic organs > 2 (HR 3.25; 95% CI [1.34–7.87], p = 0.009) were independent prognostic factors for OS. The incidence of any grade of adverse events (AEs) was 96.7% (59/61). Grade ≥ 3 AEs included neutropenia (19.7%), leukopenia (9.8%), diarrhea (3.3%), vomiting (3.3%), febrile neutropenia (1.6%), and thrombocytopenia (1.6%). No treatment-related death occurred.

Conclusion

The use of the XELOXIRI regimen with or without a targeted drug was effective, with a manageable toxicity profile in Chinese patients with mCRC.
Cancer risk in persons with new-onset anaemia: a population-based cohort study in Denmark
Authors: Boennelykke Astrid , Jensen Henry , Østgård Lene Sofie Granfeldt , Falborg Alina Zalounina , Hansen Anette Tarp , Christensen Kaj Sparle , Vedsted Peter
Published: July 2022

Background

The time interval from first symptom and sign until a cancer diagnosis significantly affects the prognosis. Therefore, recognising and acting on signs of cancer, such as anaemia, is essential. Evidence is sparse on the overall risk of cancer and the risk of specific cancer types in persons with new-onset anaemia detected in an unselected general practice population. We aimed to assess the risk of cancer in persons with new-onset anaemia detected in general practice, both overall and for selected cancer types.

Methods

This observational population-based cohort study used individually linked electronic data from laboratory information systems and nationwide healthcare registries in Denmark. We included persons aged 40–90 years without a prior history of cancer and with new-onset anaemia (no anaemia during the previous 15 months) detected in general practice in 2014–2018. We measured the incidence proportion and standardised incidence ratios of a new cancer diagnosis (all cancers except for non-melanoma skin cancers) during 12 months follow-up.

Results

A total of 48,925 persons (median [interquartile interval] age, 69 [55–78] years; 55.5% men) were included in the study. In total, 7.9% (95% confidence interval (CI): 7.6 to 8.2) of men and 5.2% (CI: 4.9 to 5.5) of women were diagnosed with cancer during 12 months. Across selected anaemia types, the highest cancer incidence proportion was seen in women with ‘anaemia of inflammation’ (15.3%, CI: 13.1 to 17.5) (ferritin > 100 ng/mL and increased C-reactive protein (CRP)) and in men with ‘combined inflammatory iron deficiency anaemia’ (19.3%, CI: 14.5 to 24.1) (ferritin < 100 ng/mL and increased CRP). For these two anaemia types, the cancer incidence across cancer types was 10- to 30-fold higher compared to the general population.

Conclusions

Persons with new-onset anaemia detected in general practice have a high cancer risk; and markedly high for ‘combined inflammatory iron deficiency anaemia’ and ‘anaemia of inflammation’. Anaemia is a sign of cancer that calls for increased awareness and action. There is a need for research on how to improve the initial pathway for new-onset anaemia in general practice.
Effectiveness of resilience training intervention on psychological capital of the underprivileged widowed women of Fasa City, Iran
Authors: Asadollahi Abdolrahim , Karimpoor Leila , Kaveh Mohammad Hossein , Ghahremani Leila
Published: July 2022

Introduction

Women heads of households (widows or divorcees) are vulnerable groups in society who face various psychological problems and have less resilience than other women. Therefore, the present study was conducted to determine the effectiveness of resilience educational intervention on the psychological capital of poor widows in Fasa city, south Iran.

Materials and Methods

In this quasi-experimental study, 120 widows covered by Imam Khomeini Relief Foundation were selected by a simple random sampling method based on a random Efron algorithm (Efron coin) and randomly assigned into two interventions and control groups (60 people each) in the second half of 2021. About 8 training sessions on resilience and psychological capital were held for the experimental group through training clips, audio transmissions, and podcasts. Data were collected using demographic characteristics forms, widowers' resilience assessment questionnaires, and Luten's psychological capital scale for testing and control before and two months after the intervention. Data were analyzed with Chi-square test, independent and paired t-test using SPSS V. 26 software.

Results

There were differences between the two groups at pretest in demographic variables and psychological capital and its subscales, and resilience and its subscales (P ≥ 0.05).. But two months after the educational intervention, a statistically significant increase was observed in the experimental group in these variables compared to the control group (p < 0.05). It indicates that there was an improvement in the outcomes from pretest to post-test within the intervention and no change in the outcomes over time within the control group.

Discussion and Conclusion

Using a resilience-based educational approach as a novelty of this research to promote psychological capital and resilience can increase resilience and psychological capital in widows. Then, considering the positive effect of this educational approach and the low cost of this intervention, it seems that the implementation of such interventions should be included in the plans related to widows.
A Canadian survey of medical students and undergraduate deans on the management of patients living with obesity
Authors: Katz Nathan J. , Lovrics Olivia , Zevin Boris
Published: July 2022

Background

With over 26% of Canadian adults living with obesity, undergraduate medical education (UGME) should prepare medical students to manage this chronic disease. It is currently unknown how the management of patients living with obesity is taught within UGME curricula in Canada. This study (1) examined the knowledge and self-reported competence of final-year medical students in managing patients living with obesity, and (2) explored how this topic is taught within UGME curricula in Canada.

Methods

We distributed two online surveys: one to final-year medical students, and another to UGME deans at 9 English-speaking medical schools in Canada. The medical student survey assessed students’ knowledge and self-reported competence in managing patients living with obesity. The dean’s survey assessed how management of patients living with obesity is taught within the UGME curriculum.

Results

One hundred thirty-three (6.9%) and 180 (9.3%) out of 1936 eligible students completed the knowledge and self-reported competence parts of the survey, respectively. Mean knowledge score was 10.5 (2.1) out of 18. Students had greatest knowledge about etiology of obesity and goals of treatment, and poorest knowledge about physiology and maintenance of weight loss. Mean self-reported competence score was 2.5 (0.86) out of 4. Students felt most competent assessing diet for unhealthy behaviors and calculating body mass index. Five (56%) out of 9 deans completed the survey. A mean of 14.6 (5.0) curricular hours were spent on teaching management of patients living with obesity. Nutrition and bariatric surgery were most frequently covered topics, with education delivered most often via large-group sessions and clinical activities.

Conclusions

Canadian medical students lack adequate knowledge and feel inadequately prepared to manage patients living with obesity. Changes to UGME curricula may help address this gap in education.
A novel splice site variant c.1183 + 1 G > C in DFNA5 causing autosomal dominant nonsyndromic hearing loss in a Chinese family
Authors: Li Qiong , Wang Shujuan , Liang Pengfei , Li Wei , Wang Jian , Fan Bei , Yang Yang , An Xiaogang , Chen Jun , Zha Dingjun
Published: July 2022

Background

The most frequent clinical presentation of autosomal dominant nonsyndromic hearing loss (ADNSHL) is bilateral, symmetrical, postlingual progressive sensorineural hearing loss, which begins with impairment at high frequencies and eventually progresses to hearing loss at all frequencies. Autosomal dominant deafness-5 (DFNA5) is a subtype of ADNSHL caused by heterozygous variants in the gasdermin E (GSDME, also known as DFNA5) gene.

Methods

Deafness gene NGS panel analysis were performed on the proband of a six-generation Chinese family with hearing loss. The co-segregation analysis between the hearing loss and the novel variant was analyzed by Sanger sequencing and pure-tone audiometry. The minigene splicing assay was performed to evaluate the potential effect of the variant on messenger RNA splicing in vitro.

Results

The family exhibited autosomal dominant, progressive, postlingual, nonsyndromic sensorineural hearing loss, which was similar to that of the previously reported DFNA5 families. A novel heterozygous splice site variant in GSDME gene intron 8 was identified, which co-segregated with the hearing loss phenotype of the family. The variant caused skipping of exon 8 in the mutant transcript, leading to the direct linking of exons 7 and 9.

Conclusions

We identified a novel GSDME splice site variant c.1183 + 1 G > C in an extended Chinese family, which led to the skipping of exon 8. The results extended the pathogenic variants spectrum of the GSDME gene, provided further support for the 'gain-of-function' mechanism of DFNA5, and afforded a molecular interpretation for these patients with ADNSHL.
Peri-event plasma PCSK9 and hsCRP after an acute myocardial infarction correlate with early deterioration of left ventricular ejection fraction: a cohort study
Authors: Silva-Bermúdez Lina S. , Vargas-Villanueva Andrea , Sánchez-Vallejo Carlos A. , Palacio Ana C. , Buitrago Andrés F. , Mendivil Carlos O.
Published: July 2022

Background

It is important to identify patients at increased risk of worsening of left ventricular ejection fraction (LVEF) after a myocardial infarction (MI). We aimed to identify the association of various potential biomarkers with LVEF impairment after an MI in South American patients.

Methods

We studied adult patients admitted to a University Hospital and diagnosed with an acute MI. Plasma concentrations of high-sensitivity C-reactive protein (hsCRP), proprotein convertase subtilisin/kexin type 9 (PCSK9), N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and heart-type fatty-acid-binding protein (FABP3) were determined in samples drawn shortly after the event. Participants had a follow-up visit at least 45 days after the event. The primary endpoint was defined as any decline in LVEF at follow-up relative to baseline.

Results

The study included 106 patients (77.4% men, 22.6% women), mean age was 64.1, mean baseline LVEF was 56.6, 19% had a prior MI. We obtained a follow-up evaluation in 100 (94.4%) of participants, mean follow-up time was 163 days. There was a significant correlation between baseline PCSK9 and hsCRP (r = 0.39, p < 0.001). Baseline hsCRP concentrations were higher in patients who developed the endpoint than in those who did not (32.1 versus 21.2 mg/L, p = 0.066). After multivariate adjustment, baseline PCSK9, male sex and age were significantly associated with impairment in LVEF. The absolute change in LVEF was inversely correlated with baseline hsCRP (standardized coefficient = − 0.246, p = 0.004).

Conclusion

High plasma levels of PCSK9 and hsCRP were associated with early decreases in LVEF after an MI in Latin American patients.
The influence of cross-regional medical treatment on total medical expenses, medical insurance payments, and out-of-pocket expenses of patients with malignant tumors in Chinese low-income areas
Authors: Zhang Bokai , Wang Haixin , Zhang Hongyu , Tian Guomei , Zhang Ting , Shi Qi , Liu Jian , Xu Jinpeng , Liu Jingchu , Wu Qunhong , Kang Zheng
Published: July 2022

Background

In recent years, due to the increasing number of cross-regional medical patients, countries around the world have issued a series of policies or regulations to reduce their out-of-pocket burden. In this context, this study intended to explore the impact of the Spatio-temporal characteristics of cross-regional medical treatment on total medical expenses, medical insurance payments, and out-of-pocket expenses of patients with malignant tumors in low-income areas.

Methods

This study included 54,904 data of cross-provincial medical treatment of malignant tumor patients insured in Heilongjiang Province, China in 2020. Firstly, Microsoft Excel 2019 and ArcGIS 10.2 were applied to conduct a descriptive analysis of the Spatio-temporal characteristics of their cross-provincial medical treatment. Then, binary and multivariate logistic regression models were used to explore the specific impact of economic level and geographical distance of medical regions on total medical expenses, medical insurance payments, and out-of-pocket expenses.

Results

The number of cross-regional medical patients showed a gradual upward trend from February to December, and fell back in January. They were concentrated in regions with high economic level and short distance from the insured region, where were more likely to form the group with high out-of-pocket expenses (AOR = 3.620, P < 0.001; AOR = 1.882, P < 0.001). While this possibility in middle-distance medical regions were less (AOR = 0.545, P < 0.001). Afterwards, two sensitivity analysis methods showed that the results were robust.

Conclusion

The number of cross-regional medical patients with malignant tumors in low-income areas is affected by seasonal factors, meanwhile, their total medical expenses, actual medical insurance payment levels, and out-of-pocket expenses are all affected by the economic level and geographical distance of medical regions. And the middle-distance medical regions may be the best choice for patients with planned cross-regional medical treatment. These provide some evidence for policymakers to improve the fairness and sustainability of medical security for cross-regional medical patients and reduce their direct economic burden of disease.
Identifying patterns of immune related cells and genes in the peripheral blood of acute myocardial infarction patients using a small cohort
Authors: Zheng Peng-Fei , Zou Qiong-Chao , Chen Lu-Zhu , Liu Peng , Liu Zheng-Yu , Pan Hong-Wei
Published: July 2022

Background

The immune system plays a vital role in the pathophysiology of acute myocardial infarction (AMI). However, the exact immune related mechanism is still unclear. This research study aimed to identify key immune-related genes involved in AMI.

Methods

CIBERSORT, a deconvolution algorithm, was used to determine the proportions of 22 subsets of immune cells in blood samples. The weighted gene co-expression network analysis (WGCNA) was used to identify key modules that are significantly associated with AMI. Then, CIBERSORT combined with WGCNA were used to identify key immune-modules. The protein–protein interaction (PPI) network was constructed and Molecular Complex Detection (MCODE) combined with cytoHubba plugins were used to identify key immune-related genes that may play an important role in the occurrence and progression of AMI.

Results

The CIBERSORT results suggested that there was a decrease in the infiltration of CD8 + T cells, gamma delta (γδ) T cells, and resting mast cells, along with an increase in the infiltration of neutrophils and M0 macrophages in AMI patients. Then, two modules (midnightblue and lightyellow) that were significantly correlated with AMI were identified, and the salmon module was found to be significantly associated with memory B cells. Gene enrichment analysis indicated that the 1,171 genes included in the salmon module are mainly involved in immune-related biological processes. MCODE analysis was used to identify four different MCODE complexes in the salmon module, while four hub genes (EEF1B2, RAC2, SPI1, and ITGAM) were found to be significantly correlated with AMI. The correlation analysis between the key genes and infiltrating immune cells showed that SPI1 and ITGAM were positively associated with neutrophils and M0 macrophages, while they were negatively associated with CD8 + T cells, γδ T cells, regulatory T cells (Tregs), and resting mast cells. The RT-qPCR validation results found that the expression of the ITGAM and SPI1 genes were significantly elevated in the AMI samples compared with the samples from healthy individuals, and the ROC curve analysis showed that ITGAM and SPI1 had a high diagnostic efficiency for the recognition of AMI.

Conclusions

Immune cell infiltration plays a crucial role in the occurrence and development of AMI. ITGAM and SPI1 are key immune-related genes that are potential novel targets for the prevention and treatment of AMI.
hUC-EVs-ATO reduce the severity of acute GVHD by resetting inflammatory macrophages toward the M2 phenotype
Authors: Su Yan , Sun Xueyan , Liu Xiao , Qu Qingyuan , Yang Liping , Chen Qi , Liu Fengqi , Li Yueying , Wang Qianfei , Huang Bo , Huang Xiao-Jun , Zhang Xiao-Hui
Published: July 2022

Background

Both extracellular vesicles from mesenchymal stromal cell-derived human umbilical cords (hUC-EVs) and arsenic trioxides (ATOs) have been demonstrated to treat acute graft-versus-host disease (aGVHD) via immunomodulation. Apart from immunomodulation, hUC-EVs have a unique function of drug delivery, which has been proposed to enhance their efficacy. In this study, we first prepared ATO-loaded hUC-EVs (hUC-EVs-ATO) to investigate the therapeutic effect and potential mechanisms of hUC-EVs-ATO in a mouse model of aGVHD after allogeneic hematopoietic stem cell transplantation (HSCT).

Methods

An aGVHD model was established to observe the therapeutic effects of hUC-EVs-ATO on aGVHD. Target organs were harvested for histopathological analysis on day 14 after transplantation. The effects of hUC-EVs-ATO on alloreactive CD4+were evaluated by flow cytometry in vivo and in vitro. Flow cytometry, RT-PCR, immunofluorescence colocalization analysis and Western blot (Wb) analysis were performed to examine macrophage polarization after hUC-EV-ATO treatment. The cytokines in serum were measured by a cytometric bead array (CBA). TEM, confocal microscopy and Wb were performed to observe the level of autophagy in macrophages. A graft-versus-lymphoma (GVL) mouse model was established to observe the role of hUC-EVs-ATO in the GVL effect.

Results

The clinical manifestations and histological scores of aGVHD in the hUC-EVs-ATO group were significantly reduced compared with those in the ATO and hUC-EVs groups. The mice receiving hUC-EVs-ATO lived longer than the control mice. Notably, hUC-EVs-ATO interfering with alloreactive CD4+T cells differentiation were observed in aGVHD mice but not in an in vitro culture system. Additional studies showed that depletion of macrophages blocked the therapeutic effects of hUC-EVs-ATO on aGVHD. Mechanistically, hUC-EVs-ATO induced autophagic flux by inhibiting mammalian target of rapamycin (mTOR) activity to repolarize M1 to M2 macrophages. Additionally, using a murine model of GVL effects, hUC-EVs-ATO were found not only to reduce the severity of aGVHD but also to preserve the GVL effects. Taken together, hUC-EVs-ATO may be promising candidates for aGVHD treatment.

Conclusions

hUC-EVs-ATO enhanced the alleviation of aGVHD severity in mice compared with ATO and hUC-EVs without weakening GVL activity. hUC-EVs-ATO promoted M1 to M2 polarization via the mTOR-autophagy pathway. hUC-EVs-ATO could be a potential therapeutic approach in aGVHD after allo-HSCT.
Mitochondria dysfunction in CD8+ T cells as an important contributing factor for cancer development and a potential target for cancer treatment: a review
Authors: Zhang Lu , Zhang Wen , Li Ziye , Lin Shumeng , Zheng Tiansheng , Hao Bingjie , Hou Yaqin , Zhang Yanfei , Wang Kai , Qin Chenge , Yue Liduo , Jin Jing , Li Ming , Fan Lihong
Published: July 2022

CD8+ T cells play a central role in anti-tumor immunity. Naïve CD8+ T cells are active upon tumor antigen stimulation, and then differentiate into functional cells and migrate towards the tumor sites. Activated CD8+ T cells can directly destroy tumor cells by releasing perforin and granzymes and inducing apoptosis mediated by the death ligand/death receptor. They also secrete cytokines to regulate the immune system against tumor cells. Mitochondria are the central hub of metabolism and signaling, required for polarization, and migration of CD8+ T cells. Many studies have demonstrated that mitochondrial dysfunction impairs the anti-tumor activity of CD8+ T cells through various pathways. Mitochondrial energy metabolism maladjustment will cause a cellular energy crisis in CD8+ T cells. Abnormally high levels of mitochondrial reactive oxygen species will damage the integrity and architecture of biofilms of CD8+ T cells. Disordered mitochondrial dynamics will affect the mitochondrial number and localization within cells, further affecting the function of CD8+ T cells. Increased mitochondria-mediated intrinsic apoptosis will decrease the lifespan and quantity of CD8+ T cells. Excessively low mitochondrial membrane potential will cause the release of cytochrome c and apoptosis of CD8+ T cells, while excessively high will exacerbate oxidative stress. Dysregulation of mitochondrial Ca2+ signaling will affect various physiological pathways in CD8+ T cells. To some extent, mitochondrial abnormality in CD8+ T cells contributes to cancer development. So far, targeting mitochondrial energy metabolism, mitochondrial dynamics, mitochondria-mediated cell apoptosis, and other mitochondrial physiological processes to rebuild the anti-tumor function of CD8+ T cells has proved effective in some cancer models. Thus, mitochondria in CD8+ T cells may be a potential and powerful target for cancer treatment in the future.
Change of renal function after short-term use of cardioprotective agents in patients with type 2 diabetes is not accurately assessed by the change of estimated glomerular filtration rate: an observational study
Authors: Kolwelter Julie , Striepe Kristina , Bosch Agnes , Kannenkeril Dennis , Ott Christian , Schiffer Mario , Schmieder Roland E.
Published: July 2022

Background

After initiating cardioprotective agents, a fall of estimated glomerular filtration rate (eGFR) has been reported in several studies. Our goal was to evaluate the accuracy of change of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR in patients with type 2 diabetes (T2D) after short-term pharmacological intervention with angiotensin-converting enzyme inhibitor, angiotensin-receptor blocker, gliptin or sodium-glucose cotransporter-2 inhibitor.

Methods

We analyzed 190 patients with T2D in the early stage of the disease, having no overt renal impairment by CKD-EPI equation. In each patient, we measured GFR (mGFR) by applying the constant infusion input clearance technique with sinistrin (Inutest; Fresenius, Linz, Austria) at baseline and after short-term (4–12 weeks) pharmacological intervention with cardioprotective agents (ramipril, telmisartan, linagliptin, metformin, empagliflozin) that potentially lead to an alteration of renal function. Simultaneously, a standardized analysis of serum creatinine was performed and eGFR was estimated by the CKD-EPI equation.

Results

Average mGFR was 111 ± 20 ml/min/1.73m2, whereas eGFR was lower with 93 ± 13 ml/min/1.73m2. The ratio eGFR/mGFR in relation to mGFR was almost curvilinear, showing an underestimation of renal function by eGFR in the upper normal range. At baseline only 80 patients (42%) lay within ± 10% of mGFR and the concordance correlation coefficient (CCC) was extremely low (− 0.07). After short-term pharmacological intervention changes in eGFR and mGFR correlated with each other (r = 0.286, p < 0.001). For example, for a given mGFR of 111 ml/min/1.73m2, a change of mGFR by ± 10% corresponded to ± 11 ml/min/1.73m2, but the confidence interval of eGFR was 25 ml/min/1.73m2. The CCC was low (0.22).

Conclusion

The agreement between eGFR by CKD-EPI and mGFR is modest and the change of renal function after short-term pharmacological intervention is not accurately and precisely reflected by the change of eGFR in patients with T2D in the early stage of their disease.
Estimating the pre- and post-diagnosis costs of tuberculosis for adults in Pakistan: household economic impact and costs mitigating strategies
Authors: Razzaq Shama , Zahidie Aysha , Fatmi Zafar
Published: July 2022

Background

Despite free tuberculosis (TB) care in Pakistan, patients still have to bear high costs, which push them into poverty. This study estimated the pre- and post-diagnosis costs households bear for TB care, and investigated coping mechanisms among adults ≥ 18 years in Karachi, Pakistan.

Methods

We conducted a cross-sectional study comprising of 516 TB patients identified with completion of at least one month intensive treatment from four public sector health facilities from two institutes in Karachi, Pakistan. A standardized questionnaire to estimate patient's costs was administered. The study outcomes were direct medical and non-medical costs, and indirect costs. The costs were estimated during pre-diagnostic and post-diagnostic phase which includes diagnostic, treatment, and hospitalization phases. A descriptive analysis including mean and standard deviation (± SD), median and interquartile range (IQR), and frequencies and proportions (%) was employed.

Results

Out of 516 TB patients, 52.1% were female with a mean age of 32.4 (± 13.7) years. The median costs per patient during the pre-diagnostic, diagnostic, treatment and hospitalization periods were estimated at USD63.8/ PKR7,377, USD24/ PKR2,755, USD10.5/ PKR1,217, and USD349.0/ PKR40,300, respectively. The total household median cost was estimated at USD129.2/ PKR14,919 per patient. The median indirect cost was estimated at USD52.0/ PKR5,950 per patient. Of total, 54.1% of patients preferred and consulted private providers in the first place at the onset of symptoms, while, 36% attended public healthcare services, 5% and 4.1% went to dispensary and pharmacy, respectively, as a first point of care.

Conclusions

TB patients bear substantial out-of-pocket costs before they are enrolled in publically funded TB programs. There should be provision of transport and food vouchers, also health insurance for in-patient treatment. This advocates a critical investigation into an existing financial support network for TB patients in Pakistan towards reducing the burden.
Freeze-all policy versus luteal phase support with low dose of human chorionic gonadotrophin for high-responder patients undergoing intracytoplasmic sperm injection on pregnancy outcomes: a retrospective cohort observational study
Authors: ELhelw Ehab Mohamed , El Serour Ahmed Gamal Elden Abou , Rady Mahmoud Salah , Abdeltawab Ahmed
Published: July 2022

Background

The literature has always controversies on the use of freeze-all policy in high-responder women performing intracytoplasmic sperm injection. In this article, we discuss the benefits of freeze-all policy on the incidence of pregnancy outcomes and the complications.

The main body of abstract

Freeze-all policy is applied to the intracytoplasmic sperm injection program by freezing of all embryos and delaying embryo transfer to another subsequent ovarian cycle, to decrease the incidence of ovarian hyperstimulation syndrome, especially in high-responder women. Unfortunately, freeze-all policy is correlated with an increase in the economic costs and more ICSI laboratory effort. Delayed embryo transfer (ET) is correlated with more anxiety among the patients. An alternative strategy is to perform fresh embryo transfer with more intensive luteal phase support to compensate for the negative effect of the GnRH agonist on the endometrial receptivity and luteal phase support.

Short conclusion

The freeze-all policy had better pregnancy rates with less incidence of moderate to severe hyperstimulation syndrome compared with original fresh embryo transfer in high-responder women performing intracytoplasmic sperm injection.
Twenty-Year Benefit From Adjuvant Goserelin and Tamoxifen in Premenopausal Patients With Breast Cancer in a Controlled Randomized Clinical Trial
Authors: Johansson Annelie , Dar Huma , van ’t Veer Laura J. , Tobin Nicholas P. , Perez-Tenorio Gizeh , Nordenskjöld Anna , Johansson Ulla , Hartman Johan , Skoog Lambert , Yau Christina , Benz Christopher C. , Esserman Laura J. , Stål Olle , Nordenskjöld Bo , Fornander Tommy , Lindström Linda S.
Published: July 2022

PURPOSE

To assess the long-term (20-year) endocrine therapy benefit in premenopausal patients with breast cancer.

METHODS

Secondary analysis of the Stockholm trial (STO-5, 1990-1997) randomly assigning 924 premenopausal patients to 2 years of goserelin (3.6 mg subcutaneously once every 28 days), tamoxifen (40 mg orally once daily), combined goserelin and tamoxifen, or no adjuvant endocrine therapy (control) is performed. Random assignment was stratified by lymph node status; lymph node–positive patients (n = 459) were allocated to standard chemotherapy (cyclophosphamide, methotrexate, and fluorouracil). Primary tumor immunohistochemistry (n = 731) and gene expression profiling (n = 586) were conducted in 2020. The 70-gene signature identified genomic low-risk and high-risk patients. Kaplan-Meier analysis, multivariable Cox proportional hazard regression, and multivariable time-varying flexible parametric modeling assessed the long-term distant recurrence-free interval (DRFI). Swedish high-quality registries allowed a complete follow-up of 20 years.

RESULTS

In estrogen receptor–positive patients (n = 584, median age 47 years), goserelin, tamoxifen, and the combination significantly improved long-term distant recurrence-free interval compared with control (multivariable hazard ratio [HR], 0.49; 95% CI, 0.32 to 0.75, HR, 0.57; 95% CI, 0.38 to 0.87, and HR, 0.63; 95% CI, 0.42 to 0.94, respectively). Significant goserelin-tamoxifen interaction was observed ( P = .016). Genomic low-risk patients (n = 305) significantly benefitted from tamoxifen (HR, 0.24; 95% CI, 0.10 to 0.60), and genomic high-risk patients (n = 158) from goserelin (HR, 0.24; 95% CI, 0.10 to 0.54). Increased risk from the addition of tamoxifen to goserelin was seen in genomic high-risk patients (HR, 3.36; 95% CI, 1.39 to 8.07). Moreover, long-lasting 20-year tamoxifen benefit was seen in genomic low-risk patients, whereas genomic high-risk patients had early goserelin benefit.

CONCLUSION

This study shows 20-year benefit from 2 years of adjuvant endocrine therapy in estrogen receptor–positive premenopausal patients and suggests differential treatment benefit on the basis of tumor genomic characteristics. Combined goserelin and tamoxifen therapy showed no benefit over single treatment. Long-term follow-up to assess treatment benefit is critical.
Oxytocin, Vasopressin, and Social Behavior: From Neural Circuits to Clinical Opportunities
Authors: Rigney Nicole , de Vries Geert J , Petrulis Aras , Young Larry J
Published: July 2022

Oxytocin and vasopressin are peptide hormones secreted from the pituitary that are well known for their peripheral endocrine effects on childbirth/nursing and blood pressure/urine concentration, respectively. However, both peptides are also released in the brain, where they modulate several aspects of social behaviors. Oxytocin promotes maternal nurturing and bonding, enhances social reward, and increases the salience of social stimuli. Vasopressin modulates social communication, social investigation, territorial behavior, and aggression, predominantly in males. Both peptides facilitate social memory and pair bonding behaviors in monogamous species. Here we review the latest research delineating the neural circuitry of the brain oxytocin and vasopressin systems and summarize recent investigations into the circuit-based mechanisms modulating social behaviors. We highlight research using modern molecular genetic technologies to map, monitor activity of, or manipulate neuropeptide circuits. Species diversity in oxytocin and vasopressin effects on social behaviors are also discussed. We conclude with a discussion of the translational implications of oxytocin and vasopressin for improving social functioning in disorders with social impairments, such as autism spectrum disorder.
ADAR2 enzymes: efficient site-specific RNA editors with gene therapy aspirations
Authors: Hajji Khadija , Sedmík Jiří , Cherian Anna , Amoruso Damiano , Keegan Liam P. , O'Connell Mary A.
Published: July 2022

The adenosine deaminase acting on RNA (ADAR) enzymes are essential for neuronal function and innate immune control. ADAR1 RNA editing prevents aberrant activation of antiviral dsRNA sensors through editing of long, double-stranded RNAs (dsRNAs). In this review, we focus on the ADAR2 proteins involved in the efficient, highly site-specific RNA editing to recode open reading frames first discovered in theGRIA2transcript encoding the key GLUA2 subunit of AMPA receptors; ADAR1 proteins also edit many of these sites. We summarize the history of ADAR2 protein research and give an up-to-date review of ADAR2 structural studies, humanADARBI(ADAR2) mutants causing severe infant seizures, and mouse disease models. Structural studies on ADARs and their RNA substrates facilitate current efforts to develop ADAR RNA editing gene therapy to edit disease-causing single nucleotide polymorphisms (SNPs). Artificial ADAR guide RNAs are being developed to retarget ADAR RNA editing to new target transcripts in order to correct SNP mutations in them at the RNA level. Site-specific RNA editing has been expanded to recode hundreds of sites in CNS transcripts inDrosophilaand cephalopods. InDrosophilaandC. elegans, ADAR RNA editing also suppresses responses to self dsRNA.
Framing and understanding the whole aspect of oral sex from social and health perspectives: a narrative review
Authors: Pakpahan Cennikon , Darmadi Darmadi , Agustinus Agustinus , Rezano Andri
Published: July 2022

Historically, oral sex is part of human sexual behaviour even though some consider it taboo, and its expression is deemed inappropriate. Human rights also stand out as technology becomes more sophisticated, leading to its practice disclosure in the 21st century. The large-scale oral sex discussion in media encourages people to express it, and there is feedback on whether it is right or not. It all depends on each person’s values. We found this sexual behaviour occurs everywhere regardless of religion, culture and race.

Pop culture influences this behaviour considerably. It can be seen in music, movies and television programmes that allude to oral sex. Numerous motivations underlying this behaviour include sexual pleasure for the sake of psychological well-being. It is undeniable that this behaviour is still controversial. There is a risk of it causing disease, but it reportedly provides many benefits.

Oral sex is not a new behaviour crossing boundaries, according to our theory. It is an old behaviour that has been highlighted because of the factors that support it. This behaviour, still considered taboo, has its disadvantages, such as sexually transmitted disease and oral cancer, but also has benefits, such as preventing preeclampsia.
Living HTA: Automating Health Technology Assessment with R
Authors: Smith Robert A. , Schneider Paul P. , Mohammed Wael
Published: July 2022

Background: Requiring access to sensitive data can be a significant obstacle for the development of health models in the Health Economics & Outcomes Research (HEOR) setting. We demonstrate how health economic evaluation can be conducted with minimal transfer of data between parties, while automating reporting as new information becomes available.

Methods: We developed an automated analysis and reporting pipeline for health economic modelling and made the source code openly available on a GitHub repository. The pipeline consists of three parts: An economic model is constructed by the consultant using pseudo data. On the data-owner side, an application programming interface (API) is hosted on a server. This API hosts all sensitive data, so that data does not have to be provided to the consultant. An automated workflow is created, which calls the API, retrieves results, and generates a report.

Results: The application of modern data science tools and practices allows analyses of data without the need for direct access – negating the need to send sensitive data. In addition, the entire workflow can be largely automated: the analysis can be scheduled to run at defined time points (e.g. monthly), or when triggered by an event (e.g. an update to the underlying data or model code); results can be generated automatically and then be exported into a report. Documents no longer need to be revised manually.

Conclusions: This example demonstrates that it is possible, within a HEOR setting, to separate the health economic model from the data, and automate the main steps of the analysis pipeline.
Gobernabilidad y conflictividad en la bahía de Pasaia (Gipuzkoa): los recortes de prensa como apoyo a la comprensión de una problemática de planificación de la interfaz ciudad-puerto
Authors: De Rosa-Giolito Enrique Rafael , Foulquier Eric
Published: July 2022

Una crisis de gobernanza portuaria y urbana se observa en la bahía de Pasaia (Gipuzkoa-País Vasco). Este trabajo pretende analizar la trayectoria de la relación puerto-ciudad, a través de la observación de la conflictividad entre los distintos actores del territorio. Mas allá del trabajo de campo y de los diferentes aportes de la bibliografía, la metodología se apoya sobre recortes de prensa local como fuente de información. Tal modalidad de investigación permite caracterizar esos actores, sus expectativas y procesos de interacción y cuantificar la intensidad de las controversias según los distintos episodios de la secuencia. Se discute la eficacia del modelo Landlord Port, el conflicto y los actores en la gestión del territorio. Las principales conclusiones de este estudio señalan que todos los actores que participan en el conflicto están legitimados para actuar, a pesar de que la ciudadanía, no se encuentra en las esferas de las decisiones. Por lo tanto, el análisis conduce a reconocer que la principal dificultad se observa en la incapacidad de los actores involucrados, a considerar la interfaz ciudad-puerto como un bien común y no como un recurso potencial.
Strong Convexity of Feasible Sets in Off-line and Online Optimization
Authors: Molinaro Marco
Published: July 2022

It is known that the curvature of the feasible set in convex optimization allows for algorithms with better convergence rates, and there is renewed interest in this topic for both off-line and online problems. In this paper, leveraging results on geometry and convex analysis, we further our understanding of the role of curvature in optimization: We first show the equivalence of two notions of curvature, namely, strong convexity and gauge bodies, proving a conjecture of Abernethy et al. As a consequence, this shows that the Frank–Wolfe–type method of Wang and Abernethy has accelerated convergence rate [Formula: see text] over strongly convex feasible sets without additional assumptions on the (convex) objective function. In online linear optimization, we identify two main properties that help explaining why/when follow the leader (FTL) has only logarithmic regret over strongly convex sets. This allows one to directly recover and slightly extend a recent result of Huang et al., and to show that FTL has logarithmic regret over strongly convex sets whenever the gain vectors are nonnegative. We provide an efficient procedure for approximating convex bodies by strongly convex ones while smoothly trading off approximation error and curvature. This allows one to extend the improved algorithms over strongly convex sets to general convex sets. As a concrete application, we extend results on online linear optimization with hints to general convex sets.

Funding: This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico [Grant Bolsa de Produtividade em Pesquisa #4310516/2017-0] Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Finance Code 001) Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (Jovem Cientista do Nosso Estado), Bolsa de Produtividade em Pesquisa #312751/2021-4 from CNPq, FAPERJ [Grant “Jovem Cientista do Nosso Estado”].
Directions for Improving State Policy to Form and Strengthen the Export Potential of Agricultural Products
Authors:   Azerbaijan Cooperation University, Bagirzadeh A.
Published: July 2022

The main purpose of the study is to analyze the current state of agricultural production, explore processing opportunities and identify areas for improving public policy to increase export potential. A statistical, systematic approach, analysis and generalization methods were used in the research work. The article provides an analysis of the role of the state in increasing the production of exportoriented agricultural products, improving competitiveness and quality, improving the technological capabilities of milk and dairy products, cotton, meat and meat products, tobacco, grapes. The research analyzes the directions of improving the state policy in increasing the production of science-intensive products by providing import-substituting agricultural products and applying scientific and technical progress. The article examines the opportunities to increase the production of agricultural products, evaluates the activities of processing enterprises, analyzes the processing potential in this area and identifies areas of state support in this area. The study analyzes the interaction of these areas, development prospects and export opportunities, and makes relevant proposals on the effectiveness and development of measures.
Economic and Mathematical Modeling of the Innovation Process in the Agro-Industrial Sector
Authors:   Azerbaijan State University of Economics, Alieva N.
Published: July 2022

Modern scientific research in the field of agriculture is increasingly based on various mathematical calculations. In practice, it is the economic and mathematical models that are of particular importance. These methods and approaches are particularly valuable and widespread in the production environment, but in the modern conditions of production and economic activity, more and more industrial economic entities are faced with the application of mathematical models in order to improve the efficiency of investment resource management.
Monitoring of Human Development in Regions of Ukraine (Integrated Approach)
Authors:   Institute of Physical Economy named after S. A. Podolynskyi, Stolyarova V. , Shynkaryuk O. ,   Institute of Physical Economy named after S. A. Podolynskyi, Stolyarov V. ,   Berdyansk University of Management and Business LLC, Antoshkin V. ,   Berdyansk University of Management and Business LLC, Goryacha O. ,   Berdyansk University of Management and Business LLC, Frolova G. ,   Berdyansk University of Management and Business LLC
Published: July 2022

The article summarizes the basics of information and methodological metrology of regional human development, the formation and development of which were approved by the Government of Ukraine in 2001, 2012 and 2017. Particular attention is paid to the problems of coordination of the assessment of the dynamics of the components of the Regional Human Development Index (RHDI) with the indicators of the National Regional Development Strategies for the periods up to 2015, 2020 and 2027. In the context of assessing the effectiveness and efficiency of the mechanism of state regulation of regional human development on the basis of its forecasting revealed the essence and content of the 4 stages of the algorithm of comprehensive rating assessment of RHDI. Methods of clustering of regions by appropriate components, methods and procedures of composition and decomposition of components of RHDI were used in order to ensure socio-economic security of regions. Differentiation of the system of indicators and procedures for monitoring regional human development at the subnational (regional) level allows to more objectively determine the socio-economic policy of regional and local executive bodies to improve the quality of life of villages, towns, cities, districts and administrative regions of Ukraine.
Organization of church parishes and church construction among the German-speaking colonists of the Tavricheskaya gubernia in the post-reform period
Authors:   Bogdan Khmelnitsky Melitopol State Pedagogical University, Zamuruitsev Oleksii , Krylova Alla ,   Bogdan Khmelnitsky Melitopol State Pedagogical University
Published: July 2022

The study of the history and culture of different peoples inhabiting or inhabiting the territory of our multinational country is still quite relevant for Russian historical science. Among these issues, a prominent place is occupied by the history of foreign colonization of the southern Ukraine, which began at the end of the 18th century. Foreign colonists (Germans, Mennonites, Bulgarians and others) took an active part in the development of these territories and played an important role in their economic and cultural development in the post-reform period. The purpose of the article is to study, using the example of the German and Mennonite settlements of the Tavricheskaya gubernia, certain aspects of the religious life of the colonist community in the southern region of modern Ukraine, related to the peculiarities of church construction and the formation of new church parishes among them. Religion played a very important role in the internal life of the German-speaking colonies in southern Ukraine. This, in particular, is evidenced by the great attention paid to the construction of churches and the opening of new church parishes by the colonial communities themselves. In turn, the tsarist government provided the colonists with a certain autonomy in their internal church affairs, but limited their religious influence on the local population. At the same time, the policy of the authorities in relation to the colonial clergy was characterized by a certain duality. On the one hand, she endowed him with significant benefits, and on the other hand, she tried to establish full control over his activities.