bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between past oral contraceptive use and the prevalence of hypertension in postmenopausal women: the fifth (2010–2012) Korea National Health and Nutrition Examination Survey (KNHANES V)
Authors: Lee JungJu , Jeong Hyunsuk , Yoon Joo Hee , Yim Hyeon Woo
Published: January 2022

Background

There is little evidence as to whether the use of oral contraceptives(OC) during the fertile years affects the development of postmenopausal hypertension. This study aimed to evaluate the association between past use of OC and development of hypertension in postmenopausal women.

Methods

This was a cross-sectional study conducted using data from the Fifth Korea National Health and Nutrition Examination Survey of postmenopausal women. Subjects were classified into three groups based on past OC use duration: nonusers, short-term users(0–30 months), and long-term users(≥ 30 months). We evaluated the development of hypertension in women after menopause. A multivariable logistic regression model was used to identify the association between the use of OC during the fertile years and the prevalence of hypertension after menopause following adjustment for potential confounding factors.

Results

Of the 3,386 postmenopausal women, 2,713 were nonusers of OC, 489 were short-term users, and 184 were long-term users. Women who had used OC for 30 months or more had a significantly greater prevalence of hypertension after menopause than those who had never taken OC. The association between taking OC for 30 months or more during the fertile years and the prevalence of hypertension after menopause was significant following adjustment for potential confounding factors (adjusted OR:1.75; 95%CI:1.12–2.74).

Conclusion

This study identified an association between past OC use and an increased prevalence of hypertension in postmenopausal women. Our results suggest that long-term use of OC during the fertile years can be an important risk factor for subsequent hypertension after menopause.
Background predictors of time to death in infancy: evidence from a survival analysis of the 2018 Nigeria DHS data
Authors: Kunnuji Michael , Eshiet Idongesit , Ahinkorah Bright Opoku , Omogbemi Temitope , Yaya Sanni
Published: January 2022

Background

Nigeria’s child health profile is quite concerning with an infant mortality rate of 67 deaths per 1000 live births and a significant slowing down in progress towards improving child health outcomes. Nigeria’s 2018 Demographic and Health Survey (DHS) suggests several bio-demographic risk factors for child death, including mother’s poor education, poverty, sex of child, age of mother, and location (rural vs urban) but studies are yet to explore the predictive power of these variables on infant survival in Nigeria.

Methods

The study extracted data for all births in the last 12 months preceding the 2018 Nigeria DHS and used the Cox proportional hazard model to predict infant survival in Nigeria. Failure in this analysis is death with two possible outcomes – dead/alive – while the survival time variable is age at death. We censored infants who were alive at the time of the study on the day of the interview. Covariates in the analysis were: age of mother, education of mother, wealth quintile, sex of child, location, region, place of delivery, and age of pregnancy.

Results

The study found that a higher education of a mother compared to no education (β = .429; p-value < 0.05); belonging to a household in the richer wealth quintile (β = .618; p-value < 0.05) or the highest quintile (β = .553; p-value < 0.05), compared to the lowest wealth quintile; and living in North West (β = 1.418; p-value < 0.05) or South East zone (β = 1.711; p-value < 0.05), significantly predict infant survival.

Conclusion

Addressing Nigeria’s infant survival problem requires interventions that give attention to the key drivers – education, socio-economic status, and socio-cultural contextual issues. We therefore recommend full implementation of the universal basic education policy, and child health education programs targeted at mothers as long- and short-term solutions to the problem of poor child health outcomes in Nigeria. We also argue in favor of better use of evidence in policy and program development in Nigeria.
Characterizing the transmission patterns of seasonal influenza in Italy: lessons from the last decade
Authors: Trentini Filippo , Pariani Elena , Bella Antonino , Diurno Giulio , Crottogini Lucia , Rizzo Caterina , Merler Stefano , Ajelli Marco
Published: January 2022

Background

Despite thousands of influenza cases annually recorded by surveillance systems around the globe, estimating the transmission patterns of seasonal influenza is challenging.

Methods

We develop an age-structured mathematical model to influenza transmission to analyze ten consecutive seasons (from 2010 to 2011 to 2019–2020) of influenza epidemiological and virological data reported to the Italian surveillance system.

Results

We estimate that 18.4–29.3% of influenza infections are detected by the surveillance system. Influenza infection attack rate varied between 12.7 and 30.5% and is generally larger for seasons characterized by the circulation of A/H3N2 and/or B types/subtypes. Individuals aged 14 years or less are the most affected age-segment of the population, with A viruses especially affecting children aged 0–4 years. For all influenza types/subtypes, the mean effective reproduction number is estimated to be generally in the range 1.09–1.33 (9 out of 10 seasons) and never exceeding 1.41. The age-specific susceptibility to infection appears to be a type/subtype-specific feature.

Conclusions

The results presented in this study provide insights on type/subtype-specific transmission patterns of seasonal influenza that could be instrumental to fine-tune immunization strategies and non-pharmaceutical interventions aimed at limiting seasonal influenza spread and burden.
Effectiveness of optimized food-based recommendation promotion to improve nutritional status and lipid profiles among Minangkabau women with dyslipidemia: A cluster-randomized trial
Authors: Gusnedi Gusnedi , Fahmida Umi , Witjaksono Fiastuti , Nurwidya Fariz , Mansyur Muchtaruddin , Djuwita Ratna , Dwiriani Cesilia Meti , Abdullah Murdani
Published: January 2022

Background

In women of Minangkabau ethnicity, a high prevalence of dyslipidemia, overweight, and obesity is thought to be closely related to poor dietary practices. Promotion of local specific food-based recommendations (FBRs) was previously found to be effective in improving dietary practice and nutrient intakes related to dyslipidemia. This study aimed to describe the effects of the FBR promotion on the nutritional status and lipid profiles of Minangkabau women with dyslipidemia.

Methods

We used a cluster-randomized design with a total subject of 123 Minangkabau women of reproductive age with dyslipidemia. They were recruited from 16 sub-villages and assigned to either the FBR group (n = 61) or the non-FBR group (n = 62). Data on body weight, height, waist circumference, and lipid profiles were collected at the baseline and the end of the trial. Linear mixed model analysis was used to analyze the effect of the intervention on nutritional status and lipid profiles.

Results

The mean effect (95% confidence interval) of the intervention on body weight, body mass index, and waist circumference for the FBR group versus the non-FBR group were -1.1 (-1.8; -0.39) kg, -0.43(-0.76; -0.11) kg/m2 and -2.1(-3.7;-0.46) mm respectively (p <0.05). The Castelli’s index in the FBR group improved, but there was no significant between-group difference in the change of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides at the end of the intervention.

Conclusion

The promotion of the FBRs positively impact the nutritional status but did not significantly affect the blood lipid profile of Minangkabau women with dyslipidemia.

Trial Registration

The trial was retrospectively registered at ClinicalTrials.gov Protocol Registration and Result System (PRS) as NCT04085874, in September 2019.
Methylprednisolone, venous thromboembolism, and association with heparin to 30 days in hospital survival in severe Covid-19 pneumonia
Authors: Go Ronaldo C. , Nyirenda Themba , Bojarian Maryam , Hosseini Davood K. , Rahim Mehek , Kim Kevin , Rose Keith M.
Published: January 2022

Background

Mortality in severe COVID-19 pneumonia is associated with thrombo-inflammation. Corticosteroids are given to attenuate the inflammation, but they are associated with thrombosis. The aims of this study were to determine the risk of venous thromboembolism between no methylprednisolone and methylprednisolone (dose versus duration) and to evaluate any synergistic dose-dependent association of heparin and methylprednisolone to 30 days in hospital survival.

Methods

This was a secondary analysis of a retrospective cohort. Patients included in this study were ≥ 18 years of age and admitted for severe COVID-19 pneumonia between March and June 2020 in 13 hospitals in New Jersey, United States. A propensity score analysis between administration of methylprednisolone and no methylprednisolone was fitted for 11 variables and Youden Index Method was used to determine cut-off between low dose and high dose methylprednisolone. Multivariate cox regression was to assess risk.

Results

In 759 patients, the incidence of venous thromboembolism was 9% of patients who received methylprednisolone and 3% of patients who did not receive methylprednisolone with a [RR 2.92 (95% CI 1.54, 5.55 P < 0.0001)]. There was a higher incidence of mechanical ventilation in the methylprednisolone group. The median d-dimer between patients with venous thromboembolism was higher compared to those without (P < 0.0003). However, the d-dimer was not statistically significant between those who had venous thromboembolism between methylprednisolone and no methylprednisolone groups (P = 0.40). There was no higher risk in high dose versus low dose [RR = 0.524 (95% CI 0.26, 1.06 P 0.4)]; however, the risk for venous thromboembolism between methylprednisolone for > 7 days and ≤ 7 days was statistically significant (RR 5.46 95% CI 2.87, 10.34 P < 0.0001). Patients who received low dose methylprednisolone and therapeutic heparin had a trend towards higher risk of mortality compared to prophylactic heparin (HR 1.81 95% CI 0.994 to 3.294) (P = 0.0522). There was no difference in 30 days in hospital survival between high dose methylprednisolone with prophylactic or therapeutic heparin (HR 0.827 95% CI 0.514 to 1.33) (P = 0.4335).

Conclusion

Methylprednisolone for > 7 days had a higher association of venous thromboembolism. There was no added benefit of therapeutic heparin to methylprednisolone on mechanically ventilated patients.
Association between blood pressure and the risk of biopsy-induced endobronchial hemorrhage during bronchoscopy
Authors: Wang Saibin , Ye Qian
Published: January 2022

Background

Hemorrhage is one of the most common complications of bronchoscopy. Although several hemorrhage risk factors have been proposed, it remains unclear whether blood pressure affects the onset of biopsy-induced endobronchial hemorrhage.

Methods

We conducted a retrospective cohort study of 643 consecutive adults with lung cancer over an approximately 4-year period (from January 2014 to February 2018) at a large tertiary care hospital. Patients were divided into the hemorrhage group and the non-hemorrhage group based on endobronchial biopsy (EBB) findings. The association between systolic pressure (SP), diastolic pressure (DP), mean arterial pressure (MAP), pulse pressure (PP), PP to DP ratio (PP/DP) and the risk of EBB-induced hemorrhage was evaluated using multivariate regression analysis and smooth curve fitting adjusted for potential confounding factors.

Results

The EBB-induced bleeding incidence was 37.8% (243/643) in our cohort. An independent association was found between PP/PD and the EBB-induced hemorrhage risk (per 1 SD, adjusted odds ratio, 0.788; 95% confidence interval, 0.653-0.951). The multivariate regression analysis performed using quartiles of PP/DP revealed that lower level of PP/DP ratio was related to a higher risk of EBB-induced hemorrhage (P for trend <0.05) after adjustment for potential confounders. However, no association was observed between SP, DP, MAP, PP and EBB-induced hemorrhage.

Conclusions

Low PP/DP was the independent risk factor for biopsy-induced endobronchial hemorrhage during bronchoscopy in patients with lung cancer.
Comparisons of biochemical parameters and diabetic ketoacidosis severity in adult patients with type 1 and type 2 diabetes
Authors: Charoenpiriya Atchara , Chailurkit Laor , Ongphiphadhanakul Boonsong
Published: January 2022

Objective

The aim of this study was to determine the differences in biochemical parameters and diabetic ketoacidosis (DKA) severity in adult patients with type 1 and type 2 diabetes and utilization of serum BHB as a biomarker for DKA resolution was also evaluated.

Materials and methods

This prospective observational study of type 1 or type 2 diabetes mellitus who were diagnosed with DKA between 01 October 2018 and 30 September 2020. The correlations between serum BHB, measured by the Ranbut assay, and pH, bicarbonate, and anion gap were examined.

Results

A total of 99 diabetes patients were diagnosed with DKA (mean age 39.4 years, 63.4% female, 53.6% T2DM). while infection was the most common precipitating factor in T2DM (43.4%), non-compliance with treatment was the most common precipitating factor in T1DM (43.5%). T1DM patients had more severe DKA more hypokalemia during treatment. However, there was no significant difference in mortality between type1 and type2 diabetes. The initial laboratories evaluation of patients did not significant differ between type1 and type2 diabetes. Serum BHB during treatment of DKA was significantly correlated with changes in serum bicarbonate (r = − 0.64), serum anion gap (r = 0.84), and venous pH (r = − 0.6). The serum BHB levels corresponding to HCO3 levels for DKA severity were 4.5, 5.7, and 5.9 mmol/L in mild, moderate, and severe DKA, respectively. The serum BHB level of < 1 mmol/L had 73.7% sensitivity and 100% specificity to predict DKA resolution. Median time to resolution of DKA was 12 h with an optimized BHB cut-off value of < 1 mmol/L. There were no significant difference in time to resolution of DKA in the patients with type 1 and type 2 diabetes.

Conclusions

There are no differences in DKA-related biochemical parameters between type 1 and type 2 diabetes patients. The present findings suggest that DKA should be assessed and treated similarly, regardless of its occurrence in type 1 or type 2 diabetes patients.
Hypoglycemia with lactic acidosis caused by a new MRPS2 gene mutation in a Chinese girl: a case report
Authors: Liu ChangZhi , Zhou WeiRan , Liu QuanE , Peng ZaiXin
Published: January 2022

Background

Mitochondrial ribosomal protein S2 (MRPS2) gene mutation, which is related to severe hypoglycemia and lactic acidosis, is rarely reported globally.

Case presentation

We report a case of a new MRPS2 gene mutation in a Chinese girl who presented with hypoglycemia and lactic acidosis. A homozygous C.412C > G variant that could cause complex oxidative phosphorylation deficiency and had not been reported before was identified. The clinical manifestations included recurrent vomiting, hypoglycemia, lactic acidosis, sensorineural hearing loss, and gall bladder calculi. Hypoglycemia and lactic acidosis improved after the administration of sugary liquid and supportive treatments.

Conclusions

Recurrent hypoglycemia with lactic acidosis and sensorineural hearing loss should lead to suspicion of mitochondrial defects and the early refinement of genetic tests.
Vitamin D deficiency associations with metabolic, bone turnover and adverse general health markers in community free living adults
Authors: Gariballa Salah , Yasin Javed , Abluwi Ghada , Al Essa Awad
Published: January 2022

Background

Although there is some evidence that vitamin D deficiency is highly prevalent in the Middle East, however its health impact is still not clear. The aim of this study was to assess the prevalence, causes and health implications of vitamin D deficiency in local United Arab Emirates (UAE) citizens.

Methods

A cross-sectional study was conducted on community free living adults living in the city of Al Ain, UAE. Following informed written consent eligible subject’s blood and urine samples were taken for measurements of vitamin D [25(OH)D], metabolic and bone turnover markers. Clinical assessment that includes general and self-rated health, muscle health, and physical activity were also performed.

Results

A total of 648 subjects (491 female) were included in this analysis. Their mean (SD) age was 38 (12) years. Mean 25(OH)D was 24 ng/ml (range: 4–67) with 286 (44%) subjects found to have vitamin D deficiency (< 20 ng/ml), 234 (36%) subjects have insufficiency (20-32 ng/ml) and 128 (20%) subjects have optimal concentrations (> 32 ng/ml). 25(OH)D concentrations were significantly higher in local indigenous UAE subjects compared to other Arab expatriates (p = 0.071). Although there were no statistically significant differences in clinical markers between groups, however, utra-sensitive C-reactive protein (us-CRP), parathyroid hormone (PTH), body mass index (BMI) and the bone markers U-PYD and PYD/CR were higher in vitamin D deficient older subjects aged ≥50 years and female subjects younger than 50 years respectively compared to those with insufficiency or optimal concentrations (p value < 0.05. Multiple logistic regression analysis revealed significant and independent association between 25(OH)D status and age and sex (p < 0.05).

Conclusion

Older subjects with vitamin D deficiency have increased BMI, inflammation and PTH compared with those with insufficiency or optimal concentrations. Co-existence of obesity and vitamin D deficiency may have increased adverse health effects.
Preference for initiation of end-of-life care discussion in Indonesia: a quantitative study
Authors: Eng Venita , Hewitt Victoria , Kekalih Aria
Published: January 2022

Background

Initiating discussion about death and dying is often considered a difficult topic for healthcare providers, thus there is a need for further research to understand this area, particularly in developing countries. The aim of this study was to describe preferences for the initiation of end-of-life care discussions in Indonesia, comparing the general population and health care professionals.

Methods

This cross-sectional, descriptive study analysed quantitative data from 368 respondents to an online questionnaire (255 general population (69%); 113 healthcare professionals (31%)) utilizing consecutive sampling and snowball sampling methods.

Results

Overall, most respondents (80%) stated that they would like to discuss end-of-life issues with a healthcare professional in the case of terminal illness. This was more marked amongst healthcare professionals compared with the general population (94% vs. 75%, respectively, p < 0,001). The preferred time for discussion was at first diagnosis (68% general population, 52% healthcare professionals, p = 0.017) and the preferred person to start the discussion was the doctor (59% general population, 71% healthcare professionals, p = 0.036). Fewer respondents wanted to know about prognosis compared to diagnosis (overall 76% v 93% respectively).

Conclusion

Doctors have vital role in end-of-life care discussion, and attempts should be made to encourage physicians to initiate these conversations and respond to patient’s requests when needed. These findings contribute to the existing body of knowledge in this area of practice, with focus on a developing country. The role of socio-cultural influences on these conversations warrants further research, in order to develop practical resources to support clinicians to appropriately conduct end-of-life care discussions with their patients and to provide data for policymakers to develop services.
Priority and age specific vaccination algorithm for the pandemic diseases: a comprehensive parametric prediction model
Authors: Tutsoy Onder , Tanrikulu Mahmud Yusuf
Published: January 2022

Background

There have been several destructive pandemic diseases in the human history. Since these pandemic diseases spread through human-to-human infection, a number of non-pharmacological policies has been enforced until an effective vaccine has been developed. In addition, even though a vaccine has been developed, due to the challenges in the production and distribution of the vaccine, the authorities have to optimize the vaccination policies based on the priorities. Considering all these facts, a comprehensive but simple parametric model enriched with the pharmacological and non-pharmacological policies has been proposed in this study to analyse and predict the future pandemic casualties.

Method

This paper develops a priority and age specific vaccination policy and modifies the non-pharmacological policies including the curfews, lockdowns, and restrictions. These policies are incorporated with the susceptible, suspicious, infected, hospitalized, intensive care, intubated, recovered, and death sub-models. The resulting model is parameterizable by the available data where a recursive least squares algorithm with the inequality constraints optimizes the unknown parameters. The inequality constraints ensure that the structural requirements are satisfied and the parameter weights are distributed proportionally.

Results

The results exhibit a distinctive third peak in the casualties occurring in 40 days and confirm that the intensive care, intubated, and death casualties converge to zero faster than the susceptible, suspicious, and infected casualties with the priority and age specific vaccination policy. The model also estimates that removing the curfews on the weekends and holidays cause more casualties than lifting the restrictions on the people with the chronic diseases and age over 65.

Conclusion

Sophisticated parametric models equipped with the pharmacological and non-pharmacological policies can predict the future pandemic casualties for various cases.
Elevated levels of interleukin-12/23p40 may serve as a potential indicator of dysfunctional heart rate variability in type 2 diabetes
Authors: Wegeberg A. M. , Okdahl T. , Riahi S. , Ejskjaer N. , Pociot F. , Størling J. , Brock B. , Brock C.
Published: January 2022

Background

Systemic inflammatory processes plausibly contribute to the development of cardiovascular complications, causing increased morbidity and mortality in type 2 diabetes. Circulating inflammatory markers, i.e., interleukin (IL)-6 and tumour necrosis factor-α, are associated with neurocardiac measures. We examined a broad panel of various inflammatory and inflammation-related serum markers to obtain more detailed insight into the possible neuro-immune interaction between cardiovascular regulation and systemic level of inflammation.

Methods

Serum samples from 100 participants with type 2 diabetes were analysed. Heart rate variability, cardiovascular autonomic reflex tests, and cardiac vagal tone tests were performed based on electrocardiographic readings. Data regarding covariates (demographic-, diabetes-, and cardiovascular risk factors) were registered.

Results

Increased serum levels of IL-12/IL-23p40 (p  < 0.01) and intercellular adhesion molecule (ICAM)-1 (p  < 0.007) were associated with diminished heart rate variability measures. After all adjustments, the associations between IL-12/23p40, SDANN and VLF persisted (p  = 0.001). Additionally, serum levels of vascular endothelial growth factor (VEGF)-C were associated with response to standing (p  = 0.005).

Discussion

The few but robust associations between neurocardiac regulation and serum markers found in this study suggest systemic changes in proinflammatory, endothelial, and lymphatic function, which collectively impacts the systemic cardiovascular function. Our results warrant further exploration of IL-12/IL-23p40, ICAM-1, and VEGF-C as possible cardiovascular biomarkers in T2D that may support future decisions regarding treatment strategies for improved patient care.
Evaluation of the long-term prognostic ability of triglyceride-glucose index for elderly acute coronary syndrome patients: a cohort study
Authors: Jiao Yang , Su Yongkang , Shen Jian , Hou Xiaoling , Li Ying , Wang Jihang , Liu Bing , Qiu Dongfeng , Sun Zhijun , Chen Yundai , Xi Qing , Shen Mingzhi , Fu Zhenhong
Published: January 2022

Background

With the advancement of the world population aging, more attention should be paid to the prognosis of elderly patients with acute coronary syndrome (ACS). Triglyceride-glucose (TyG) index is a reliable indicator of insulin resistance (IR) and is closely related to traditional risk factors of cardiovascular disease (CVD). However, the effect of TyG index on the prognosis of long-term adverse events in elderly ACS patients has not been reported. This study evaluated the prognostic power of TyG index in predicting adverse events in elderly ACS patients.

Methods

In this study, 662 ACS patients > 80 years old who were hospitalized from January 2006 to December 2012 were enrolled consecutively and the general clinical data and baseline blood biochemical indicators were collected. The follow-up time after discharge was 40–120 months (median, 63 months; interquartile range, 51‒74 months). In addition, the following formula was used to calculate the TyG index: Ln [fasting TG (mg/dL) × FBG (mg/dL)/2], and patients were divided into three groups according to the tertile of the TyG index.

Results

The mean age of the subjects was 81.87 ± 2.14 years, the proportion of females was 28.10%, and the mean TyG index was 8.76 ± 0.72. The TyG index was closely associated with the traditional risk factors of CVD. In the fully-adjusted Cox regression model, the Hazard ratio (95% CI) of all-cause mortality (in tertile 3) was 1.64 (1.06, 2.54) and major adverse cardiac event (MACE) (in tertile 3) was 1.36 (1.05, 1.95) for each SD increase in the TyG index. The subgroup analyses also confirmed the significant association of the TyG index and long-term prognosis.

Conclusion

The TyG index is an independent predictor of long-term all-cause mortality and MACE in elderly ACS patients.
Light-induced production of isobutanol and 3-methyl-1-butanol by metabolically engineered cyanobacteria
Authors: Kobayashi Shunichi , Atsumi Shota , Ikebukuro Kazunori , Sode Koji , Asano Ryutaro
Published: January 2022

Background

Cyanobacteria are engineered via heterologous biosynthetic pathways to produce value-added chemicals via photosynthesis. Various chemicals have been successfully produced in engineered cyanobacteria. Chemical inducer-dependent promoters are used to induce the expression of target biosynthetic pathway genes. A chemical inducer is not ideal for large-scale reactions owing to its high cost; therefore, it is important to develop scaling-up methods to avoid their use. In this study, we designed a green light-inducible alcohol production system using the CcaS/CcaR green light gene expression system in the cyanobacterium Synechocystis sp. PCC 6803 (PCC 6803).

Results

To establish the green light-inducible production of isobutanol and 3-methyl-1-butanol (3MB) in PCC 6803, keto-acid decarboxylase (kdc) and alcohol dehydrogenase (adh) were expressed under the control of the CcaS/CcaR system. Increases in the transcription level were induced by irradiation with red and green light without severe effects on host cell growth. We found that the production of isobutanol and 3MB from carbon dioxide (CO2) was induced under red and green light illumination and was substantially repressed under red light illumination alone. Finally, production titers of isobutanol and 3MB reached 238 mg L−1 and 75 mg L−1, respectively, in 5 days under red and green light illumination, and these values are comparable to those reported in previous studies using chemical inducers.

Conclusion

A green light-induced alcohol production system was successfully integrated into cyanobacteria to produce value-added chemicals without using expensive chemical inducers. The green light-regulated production of isobutanol and 3MB from CO2 is eco-friendly and cost-effective. This study demonstrates that light regulation is a potential tool for producing chemicals and increases the feasibility of cyanobacterial bioprocesses.

Graphical Abstract
Functional characterization of 5′ UTR cis-acting sequence elements that modulate translational efficiency in Plasmodium falciparum and humans
Authors: Garcia Valentina E. , Dial Rebekah , DeRisi Joseph L.
Published: January 2022

Background

The eukaryotic parasite Plasmodium falciparum causes millions of malarial infections annually while drug resistance to common anti-malarials is further confounding eradication efforts. Translation is an attractive therapeutic target that will benefit from a deeper mechanistic understanding. As the rate limiting step of translation, initiation is a primary driver of translational efficiency. It is a complex process regulated by both cis and trans acting factors, providing numerous potential targets. Relative to model organisms and humans, P. falciparum mRNAs feature unusual 5′ untranslated regions suggesting cis-acting sequence complexity in this parasite may act to tune levels of protein synthesis through their effects on translational efficiency.

Methods

Here, in vitro translation is deployed to compare the role of cis-acting regulatory sequences in P. falciparum and humans. Using parasite mRNAs with high or low translational efficiency, the presence, position, and termination status of upstream “AUG”s, in addition to the base composition of the 5′ untranslated regions, were characterized.

Results

The density of upstream “AUG”s differed significantly among the most and least efficiently translated genes in P. falciparum, as did the average “GC” content of the 5′ untranslated regions. Using exemplars from highly translated and poorly translated mRNAs, multiple putative upstream elements were interrogated for impact on translational efficiency. Upstream “AUG”s were found to repress translation to varying degrees, depending on their position and context, while combinations of upstream “AUG”s had non-additive effects. The base composition of the 5′ untranslated regions also impacted translation, but to a lesser degree. Surprisingly, the effects of cis-acting sequences were remarkably conserved between P. falciparum and humans.

Conclusions

While translational regulation is inherently complex, this work contributes toward a more comprehensive understanding of parasite and human translational regulation by examining the impact of discrete cis-acting features, acting alone or in context.
Evaluating performance of multiplex real time PCR for the diagnosis of malaria at elimination targeted low transmission settings of Ethiopia
Authors: Belachew Mahlet , Wolde Mistire , Nega Desalegn , Gidey Bokretsion , Negash Legessie , Assefa Ashenafi , Tasew Geremew , Woyessa Adugna , Abera Adugna
Published: January 2022

Background

Malaria incidence has declined in Ethiopia in the past 10 years. Current malaria diagnostic tests, including light microscopy and rapid antigen-detecting diagnostic tests (RDTs) cannot reliably detect low-density infections. Studies have shown that nucleic acid amplification tests are highly sensitive and specific in detecting malaria infection. This study took place with the aim of evaluating the performance of multiplex real time PCR for the diagnosis of malaria using patient samples collected from health facilities located at malaria elimination targeted low transmission settings in Ethiopia.

Methods

A health facility-based, cross-sectional survey was conducted in selected malaria sentinel sites. Malaria-suspected febrile outpatients referred to laboratory for malaria testing between December 2019 and March 2020 was enrolled into this study. Sociodemographic information and capillary blood samples were collected from the study participants and tested at spot with RDTs. Additionally, five circles of dry blood spot (DBS) samples on Whatman filter paper and thick and thin smear were prepared for molecular testing and microscopic examination, respectively. Multiplex real time PCR assay was performed at Ethiopian Public Health Institute (EPHI) malaria laboratory. The performance of multiplex real time PCR assay, microscopy and RDT for the diagnosis of malaria was compared and evaluated against each other.

Results

Out of 271 blood samples, multiplex real time PCR identified 69 malaria cases as Plasmodium falciparum infection, 16 as Plasmodium vivax and 3 as mixed infections. Of the total samples, light microscopy detected 33 as P. falciparum, 18 as P. vivax, and RDT detected 43 as P. falciparum, 17 as P. vivax, and one mixed infection. Using light microscopy as reference test, the sensitivity and specificity of multiplex real time PCR were 100% (95% CI (93–100)) and 83.2% (95% CI (77.6–87.9)), respectively. Using multiplex real time PCR as a reference, light microscopy and RDT had sensitivity of 58% (95% CI 46.9–68.4) and 67% (95% CI 56.2–76.7); and 100% (95% CI 98–100) and 98.9% (95% CI 96–99.9), respectively. Substantial level of agreement was reported between microscopy and multiplex real time PCR results with kappa value of 0.65.

Conclusions

Multiplex real-time PCR had an advanced performance in parasite detection and species identification on febrile patients’ samples than did microscopy and RDT in low malaria transmission settings. It is highly sensitive malaria diagnostic method that can be used in malaria elimination programme, particularly for community based epidemiological samples. Although microscopy and RDT had reduced performance when compared to multiplex real time PCR, still had an acceptable performance in diagnosis of malaria cases on patient samples at clinical facilities.
Ultrasensitive dynamic light scattering immunosensing platform for NT-proBNP detection using boronate affinity amplification
Authors: Hu Jiaqi , Ding Lu , Chen Jing , Fu Jinhua , Zhu Kang , Guo Qian , Huang Xiaolin , Xiong Yonghua
Published: January 2022

Herein, we reported a new dynamic light scattering (DLS) immunosensing technology for the rapid and sensitive detection of glycoprotein N-terminal pro-brain natriuretic peptide (NT-proBNP). In this design, the boronate affinity recognition based on the interaction of boronic acid ligands and cis-diols was introduced to amplify the nanoparticle aggregation to enable highly sensitive DLS transduction, thereby lowering the limit of detection (LOD) of the methodology. After covalently coupling with antibodies, magnetic nanoparticles (MNPs) were employed as the nanoprobes to selectively capture trace amount of NT-proBNP from complex samples and facilitate DLS signal transduction. Meanwhile, silica nanoparticles modified with phenylboronic acid (SiO2@PBA) were designed as the crosslinking agent to bridge the aggregation of MNPs in the presence of target NT-proBNP. Owing to the multivalent and fast affinity recognition between NT-proBNP containing cis-diols and SiO2@PBA, the developed DLS immunosensor exhibited charming advantages over traditional immunoassays, including ultrahigh sensitivity with an LOD of 7.4 fg mL−1, fast response time (< 20 min), and small sample consumption (1 μL). The DLS immunosensor was further characterized with good selectivity, accuracy, precision, reproducibility, and practicability. Collectively, this work demonstrated the promising application of the designed boronate affinity amplified-DLS immunosensor for field or point-of-care testing of cis-diol-containing molecules.

Graphical Abstract
Extracellular matrix-degrading STING nanoagonists for mild NIR-II photothermal-augmented chemodynamic-immunotherapy
Authors: Zhan Meixiao , Yu Xiangrong , Zhao Wei , Peng Yongjun , Peng Shaojun , Li Jingchao , Lu Ligong
Published: January 2022

Regulation of stimulator of interferon genes (STING) pathway using agonists can boost antitumor immunity for cancer treatment, while the rapid plasma clearance, limited membrane permeability, and inefficient cytosolic transport of STING agonists greatly compromise their therapeutic efficacy. In this study, we describe an extracellular matrix (ECM)-degrading nanoagonist (dNAc) with second near-infrared (NIR-II) light controlled activation of intracellular STING pathway for mild photothermal-augmented chemodynamic-immunotherapy of breast cancer. The dNAc consists of a thermal-responsive liposome inside loading with ferrous sulfide (FeS2) nanoparticles as both NIR-II photothermal converters and Fenton catalysts, 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) as the STING agonist, and an ECM-degrading enzyme (bromelain) on the liposome surface. Mild heat generated by dNAc upon NIR-II photoirradiation improves Fenton reaction efficacy to kill tumor cells and cause immunogenic cell death (ICD). Meanwhile, the generated heat triggers a controlled release of cGAMP from thermal-responsive liposomes to active STING pathway. The mild photothermal activation of STING pathway combined with ICD promotes anti-tumor immune responses, which leads to improved infiltration of effector T cells into tumor tissues after bromelain-mediated ECM degradation. As a result, after treatment with dNAc upon NIR-II photoactivation, both primary and distant tumors in a murine mouse model are inhibited and the liver and lung metastasis are effectively suppressed. This work presents a photoactivatable system for STING pathway and combinational immunotherapy with improved therapeutic outcome.

Graphical Abstract
Systematic review of performance-enhancing health worker supervision approaches in low- and middle-income countries
Authors: Deussom Rachel , Mwarey Doris , Bayu Mekdelawit , Abdullah Sarah S. , Marcus Rachel
Published: January 2022

Background

The strength of a health system—and ultimately the health of a population—depends to a large degree on health worker performance. However, insufficient support to build, manage and optimize human resources for health (HRH) in low- and middle-income countries (LMICs) results in inadequate health workforce performance, perpetuating health inequities and low-quality health services.

Methods

The USAID-funded Human Resources for Health in 2030 Program (HRH2030) conducted a systematic review of studies documenting supervision enhancements and approaches that improved health worker performance to highlight components associated with these interventions’ effectiveness. Structured by a conceptual framework to classify the inputs, processes, and results, the review assessed 57 supervision studies since 2010 in approximately 29 LMICs.

Results

Of the successful supervision approaches described in the 57 studies reviewed, 44 were externally funded pilots, which is a limitation. Thirty focused on community health worker (CHW) programs. Health worker supervision was informed by health system data for 38 approaches (67%) and 22 approaches used continuous quality improvement (QI) (39%). Many successful approaches integrated digital supervision technologies (e.g., SmartPhones, mHealth applications) to support existing data systems and complement other health system activities. Few studies were adapted, scaled, or sustained, limiting reports of cost-effectiveness or impact.

Conclusion

Building on results from the review, to increase health worker supervision effectiveness we recommend to: integrate evidence-based, QI tools and processes; integrate digital supervision data into supervision processes; increase use of health system information and performance data when planning supervision visits to prioritize lowest-performing areas; scale and replicate successful models across service delivery areas and geographies; expand and institutionalize supervision to reach, prepare, protect, and support frontline health workers, especially during health emergencies; transition and sustain supervision efforts with domestic human and financial resources, including communities, for holistic workforce support. In conclusion, effective health worker supervision is informed by health system data, uses continuous quality improvement (QI), and employs digital technologies integrated into other health system activities and existing data systems to enable a whole system approach. Effective supervision enhancements and innovations should be better integrated, scaled, and sustained within existing systems to improve access to quality health care.
A review of the continuous professional development system for pharmacists
Authors: Batista Jorge P. B. , Torre Carla , Sousa Lobo José Manuel , Sepodes Bruno
Published: January 2022

Background

The Portuguese Pharmaceutical Society (PPS) implemented a system of Continuous Professional Development (CPD) for pharmacists in 2004. This system has evolved throughout the years, and currently all active pharmacists in Portugal are required to participate in the CPD program. Each CPD cycle takes 5 years. In each cycle, pharmacists must collect 15 CPD points, through participation in educational activities. The PPS accreditation process is managed via an online platform, where education/training providers, as well as pharmacists themselves, can submit educational activities for accreditation. Pharmacists may access their CPD status and assess their development at any point. The objective of this study was to analyze and review the educational activities submitted by providers over a 11-year period (2009–2019).

Methods

Data from activities were retrieved from the PPS CPD online platform. All educational activities were labeled according to the area of pharmaceutical professional focus, type of promoter, and activity type.

Results

During the study 3685 activities were analyzed. Over the last decade, submitted activities for accreditation increased in 52.6%. A significantly high proportion (98.9%) of these activities has been accredited. Promoters of activities were mostly pharmacies sectoral associations (29.6%), consultancy/training companies (19.6%), the PPS (18.5%), pharmaceutical industry (17.7%) and wholesalers’ consortia (9.0%). Academia represented only 2.3% of the total amount of educational activities. The most frequent topics were related to “pharmacology & pharmacotherapy” (9.9%), followed by “counselling” (9.8%) and “management & administration” (7.2%). The most accredited type of activities was face-to-face (68.9%) and e-learning trainings (13.1%).

Conclusions

This study shows increasing interest in submitting CPD activities for accreditation between 2009 and 2019, but it also demonstrates that Academia could play a more interventive role in the lifelong learning education of Portuguese pharmacists.
Argonaute-2 protects the neurovascular unit from damage caused by systemic inflammation
Authors: Machado-Pereira Marta , Saraiva Cláudia , Bernardino Liliana , Cristóvão Ana C. , Ferreira Raquel
Published: January 2022

Background

The brain vasculature plays a pivotal role in the inflammatory process by modulating the interaction between blood cells and the neurovascular unit. Argonaute-2 (Ago2) has been suggested as essential for endothelial survival but its role in the brain vasculature or in the endothelial–glial crosstalk has not been addressed. Thus, our aim was to clarify the significance of Ago2 in the inflammatory responses elicited by these cell types.

Methods

Mouse primary cultures of brain endothelial cells, astrocytes and microglia were used to evaluate cellular responses to the modulation of Ago2. Exposure of microglia to endothelial cell-conditioned media was used to assess the potential for in vivo studies. Adult mice were injected intraperitoneally with lipopolysaccharide (LPS) (2 mg/kg) followed by three daily intraperitoneal injections of Ago2 (0.4 nM) to assess markers of endothelial disruption, glial reactivity and neuronal function.

Results

Herein, we demonstrated that LPS activation disturbed the integrity of adherens junctions and downregulated Ago2 in primary brain endothelial cells. Exogenous treatment recovered intracellular Ago2 above control levels and recuperated vascular endothelial-cadherin expression, while downregulating LPS-induced nitric oxide release. Primary astrocytes did not show a significant change in Ago2 levels or response to the modulation of the Ago2 system, although endogenous Ago2 was shown to be critical in the maintenance of tumor necrosis factor-α basal levels. LPS-activated primary microglia overexpressed Ago2, and Ago2 silencing contained the inflammatory response to some extent, preventing interleukin-6 and nitric oxide release. Moreover, the secretome of Ago2-modulated brain endothelial cells had a protective effect over microglia. The intraperitoneal injection of LPS impaired blood–brain barrier and neuronal function, while triggering inflammation, and the subsequent systemic administration of Ago2 reduced or normalized endothelial, glial and neuronal markers of LPS damage. This outcome likely resulted from the direct action of Ago2 over the brain endothelium, which reestablished glial and neuronal function.

Conclusions

Ago2 could be regarded as a putative therapeutic agent, or target, in the recuperation of the neurovascular unit in inflammatory conditions.
Delta opioid receptors on nociceptive sensory neurons mediate peripheral endogenous analgesia in colitis
Authors: Mas-Orea Xavier , Basso Lilian , Blanpied Catherine , Gaveriaux-Ruff Claire , Cenac Nicolas , Dietrich Gilles
Published: January 2022

Background

Inflammatory visceral pain is endogenously controlled by enkephalins locally released by mucosal CD4+ T lymphocytes in mice. The present study aimed at identifying opioid receptor(s) expressed on nociceptive sensory nerves involved in this peripheral opioid-mediated analgesia.

Methods

The peripheral analgesia associated with the accumulation of CD4+ T lymphocytes within the inflamed colonic mucosa was assessed in conditional knockout mice specifically deleted for either of the two opioid receptors for enkephalins (i.e., µ (MOR) and δ (DOR) receptors) in Nav1.8-expressing sensory neurons in the dextran sulfate sodium (DSS)-induced colitis model.

Results

Endogenous analgesia is lost in conditional knockout mice for DOR, but not MOR at the later phase of the DSS-induced colitis. The absence of either of the opioid receptors on sensory nerves had no impact on both the colitis severity and the rate of T lymphocytes infiltrating the inflamed colonic mucosa.

Conclusion

The key role of DOR on primary afferents in relieving intestinal inflammatory pain opens new therapeutic opportunities for peripherally restricted DOR analgesics to avoid most of the side effects associated with MOR-targeting drugs used in intestinal disorders.