bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term outcomes of early initiated antiretroviral therapy in sub-Saharan children: a Cameroonian cohort study (ANRS-12140 Pediacam study, 2008–2013, Cameroon)
Authors: Ndongo Francis Ateba , Tejiokem Mathurin Cyrille , Penda Calixte Ida , Ndiang Suzie Tetang , Ndongo Jean-Audrey , Guemkam Georgette , Sofeu Casimir Ledoux , Tagnouokam-ngoupo Paul Alain , Kfutwah Anfumbom , Msellati Philippe , Faye Albert , Warszawski Josiane
Published: April 2021

Background

In most studies, the virological response is assessed during the first two years of antiretroviral treatment initiated in HIV-infected infants. However, early initiation of antiretroviral therapy exposes infants to very long-lasting treatment. Moreover, maintaining viral suppression in children is difficult. We aimed to assess the virologic response and mortality in HIV-infected children after five years of early initiated antiretroviral treatment (ART) and identify factors associated with virologic success in Cameroon.

Methods

In the ANRS-12140 Pediacam cohort study, 2008–2013, Cameroon, we included all the 149 children who were still alive after two years of early ART. Virologic response was assessed after 5 years of treatment. The probability of maintaining virologic success between two and five years of ART was estimated using Kaplan-Meier curve. The immune status and mortality were also studied at five years after ART initiation. Factors associated with a viral load < 400 copies/mL in children still alive at five years of ART were studied using logistic regressions.

Results

The viral load after five years of early ART was suppressed in 66.8% (60.1–73.5) of the 144 children still alive and in care. Among the children with viral suppression after two years of ART, the probability of maintaining viral suppression after five years of ART was 64.0% (54.0–74.0). The only factor associated with viral suppression after five years of ART was achievement of confirmed virological success within the first two years of ART (OR = 2.7 (1.1–6.8); p = 0.033).

Conclusions

The probability of maintaining viral suppression between two and five years of early initiated ART which was quite low highlights the difficulty of parents to administer drugs daily to their children in sub-Saharan Africa. It also stressed the importance of initial viral suppression for achieving and maintaining virologic success in the long-term. Further studies should focus on identifying strategies that would enhance better retention in care and improved adherence to treatment within the first two years of ART early initiated in Sub-Saharan HIV-infected children.
Projections of disability-adjusted life years for major diseases due to a change in vegetable intake in 2017–2040 in Japan
Authors: Tanaka Shiori , Yoneoka Daisuke , Ishizuka Aya , Ueda Peter , Nakamura Keiji , Uneyama Hisayuki , Hayashi Naoki , Shibuya Kenji , Nomura Shuhei
Published: April 2021

Background

Low vegetable intake is one of the key dietary risk factors known to be associated with a range of health problems, including cardiovascular diseases (CVDs), cancer, and diabetes and kidney diseases (DKDs). Using data from Japan’s National Health and Nutrition Surveys and the Global Burden of Diseases study in 2017, this study aimed to forecast the impact of change in vegetable intake on disability-adjusted life years (DALYs) between 2017 and 2040 for three diseases.

Methods

We generated a three-component model of cause-specific DALYs, including changes in major behavioural and metabolic risk predictors, the socio-demographic index and an autoregressive integrated moving average model to project future DALY rates for 2017–2040 using the data between 1990 and 2016. Data on Vegetable consumption and risk predictors, and DALY rate were obtained from Japan’s National Health and Nutrition Surveys and the Global Burden of Diseases Study in 2017. We also modelled three scenarios of better, moderate and worse cases to evaluate the impact of change in vegetable consumption on the DALY rates for three diseases (CVDs, cancer, and DKDs).

Results

Projected mean vegetable intake in the total population showed a decreasing trend through 2040 to 237.7 g/day. A significant difference between the reference scenario and the better case scenario was observed with un-overlapped 95% prediction intervals of DALY rates in females aged 20–49 years (− 8.0%) for CVDs, the total population for cancer (− 5.6%), and in males (− 8.2%) and females (− 13.7%) for DKDs.

Conclusions

Our analysis indicates that increased vegetable consumption would have a significant reduction in the burdens of CVDs, cancer and DKDs in Japan. By estimating the disease burden attributable to low vegetable intake under different scenarios of future vegetable consumption, our study can inform the design of targeted interventions for public health challenges.
Attitudes, behaviours and barriers to public health measures for COVID-19: a survey to inform public health messaging
Authors: Lang Raynell , Benham Jamie L. , Atabati Omid , Hollis Aidan , Tombe Trevor , Shaffer Blake , Burns Katharina Kovacs , MacKean Gail , Léveillé Tova , McCormack Brandi , Sheikh Hasan , Fullerton Madison M. , Tang Theresa , Boucher Jean-Christophe , Constantinescu Cora , Mourali Mehdi , Manns Braden J. , Marshall Deborah A. , Hu Jia , Oxoby Robert J.
Published: April 2021

Background

Public support of public health measures including physical distancing, masking, staying home while sick, avoiding crowded indoor spaces and contact tracing/exposure notification applications remains critical for reducing spread of COVID-19. The aim of our work was to understand current behaviours and attitudes towards public health measures as well as barriers individuals face in following public health measures. We also sought to identify attitudes persons have regarding a COVID-19 vaccine and reasons why they may not accept a vaccine.

Methods

A cross-sectional online survey was conducted in August 2020, in Alberta, Canada in persons 18 years and older. This survey evaluated current behaviours, barriers and attitudes towards public health measures and a COVID-19 vaccine. Cluster analysis was used to identify key patterns that summarize data variations among observations.

Results

Of the 60 total respondents, the majority of persons were always or often physically distancing (73%), masking (65%) and staying home while sick (67%). Bars/pubs/lounges or nightclubs were visited rarely or never by 63% of respondents. Persons identified staying home while sick to provide the highest benefit (83%) in reducing spread of COVID-19. There were a large proportion of persons who had not downloaded or used a contact tracing/exposure notification app (77%) and who would not receive a COVID-19 vaccine when available (20%) or were unsure (12%). Reporting health authorities as most trusted sources of health information was associated with greater percentage of potential uptake of vaccine but not related to contact tracing app download and use. Individuals with lower concern of getting and spreading COVID-19 showed the least uptake of public health measures except for avoiding public places such as bars. Lower concern regarding COVID-19 was also associated with more negative responses to taking a potential COVID-19 vaccine.

Conclusion

These results suggest informational frames and themes focusing on individual risks, highlighting concern for COVID-19 and targeting improving trust for health authorities may be most effective in increasing public health measures. With the ultimate goal of preventing spread of COVID-19, understanding persons’ attitudes towards both public health measures and a COVID-19 vaccine remains critical to addressing barriers and implementing targeted interventions and messaging to improve uptake.
Differences in clinical knowledge levels between residents in two post‐graduate rotation programmes in Japan
Authors: Muroya Saki , Ohde Sachiko , Takahashi Osamu , Jacobs Joshua , Fukui Tsuguya
Published: April 2021

Background

In Japan, between 2010 and 2020, there were two post-graduate training curricula for post-graduate medical education, as follows: comprehensive rotation programmes (CRPs), which require rotation in at least seven clinical departments; and limited rotation programmes (LRPs), which require rotation in fewer clinical departments. The curriculum that should be used for standardized Japanese post-graduate training has long been debated. Multiple studies show that post-graduate trainees who trained with CRPs were more satisfied and confident and gained more clinical experience than those who trained with LRPs. However, a comparison of objective measurements of the clinical knowledge of Japanese post-graduate trainees has not been reported. The aim of this study is to objectively measure and compare the clinical knowledge of trainees in CRPs and LRPs using a component of the Professional and Linguistic Assessment Board test (PLAB test).

Methods

A nationwide cross-sectional study was conducted in February and March 2020. Post-graduate trainees who graduated from medical school were voluntarily recruited from general hospitals in Japan. To objectively measure the trainees’ basic clinical knowledge, the PLAB test was adapted from the UK. The cut-off point was set at 63%, as recommended by the UK General Medical Council. A statistical analysis was conducted to determine whether post-graduate programme differences contributed to the trainees’ test scores.

Results

Twenty-two facilities volunteered to participate after recruitment, and 97 trainees from 19 facilities participated in the study. Thirty-one participants (32%) were in a CRP, and 66 participants (68%) were in an LRP. According to multiple logistic regression, the adjusted odds ratio of CRP trainees being in the high-scoring group was 5.16 (95% CI: 1.28-20.73, p<0.05). Mean differences in the scores in paediatrics, mental health and neurology were statistically higher among CRP trainees than LRP trainees.

Conclusion

Post-graduate trainees who were in a CRP had better basic clinical competence knowledge (PLAB test) scores and performed better when tested in a wider range of subspecialties. Not only exam performance but also clinical performance and the longitudinal trend of trainees’ competency in post-graduate medical training should be evaluated in future studies.
The relationship between time to diagnose and diagnostic accuracy among internal medicine residents: a randomized experiment
Authors: Staal J. , Alsma J. , Mamede S. , Olson A. P. J. , Prins-van Gilst G. , Geerlings S. E. , Plesac M. , Sundberg M. A. , Frens M. A. , Schmidt H. G. , Van den Broek W. W. , Zwaan L.
Published: April 2021

Background

Diagnostic errors have been attributed to cognitive biases (reasoning shortcuts), which are thought to result from fast reasoning. Suggested solutions include slowing down the reasoning process. However, slower reasoning is not necessarily more accurate than faster reasoning. In this study, we studied the relationship between time to diagnose and diagnostic accuracy.

Methods

We conducted a multi-center within-subjects experiment where we prospectively induced availability bias (using Mamede et al.’s methodology) in 117 internal medicine residents. Subsequently, residents diagnosed cases that resembled those bias cases but had another correct diagnosis. We determined whether residents were correct, incorrect due to bias (i.e. they provided the diagnosis induced by availability bias) or due to other causes (i.e. they provided another incorrect diagnosis) and compared time to diagnose.

Results

We did not successfully induce bias: no significant effect of availability bias was found. Therefore, we compared correct diagnoses to all incorrect diagnoses. Residents reached correct diagnoses faster than incorrect diagnoses (115 s vs. 129 s,p < .001). Exploratory analyses of cases where bias was induced showed a trend of time to diagnose for bias diagnoses to be more similar to correct diagnoses (115 s vs 115 s,p = .971) than to other errors (115 s vs 136 s,p = .082).

Conclusions

We showed that correct diagnoses were made faster than incorrect diagnoses, even within subjects. Errors due to availability bias may be different: exploratory analyses suggest a trend that biased cases were diagnosed faster than incorrect diagnoses. The hypothesis that fast reasoning leads to diagnostic errors should be revisited, but more research into the characteristics of cognitive biases is important because they may be different from other causes of diagnostic errors.
Identification of a novel LAMA2 c.2217G > A, p.(Trp739*) mutation in a Moroccan patient with congenital muscular dystrophy: a case report
Authors: El Kadiri Youssef , Ratbi Ilham , Laarabi Fatima Zahra , Kriouile Yamna , Sefiani Abdelaziz , Lyahyai Jaber
Published: April 2021

Background

Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a rare autosomal recessive genetic condition caused by deleterious mutations in the LAMA2 gene encoding the laminin-α2 chain. It is the most frequent subtype of congenital muscular dystrophies (CMDs) characterized by total laminin-α2 deficiency with muscle weakness at birth or in the first six months of life. To the best of our knowledge, this study reports the first molecular diagnosis and genetic defect of this heterogeneous form of CMD performed in a Moroccan medical genetic center using next-generation sequencing (NGS). It allows us to expand the mutational spectrum of the LAMA2 gene.

Case presentation

We report the case of a female Moroccan child with clinical and paraclinical features in favor of a CMD. She has global congenital hypotonia with generalized muscle weakness, psychomotor retardation, increased serum creatine kinase, and normal brain scan at the age of six months. Targeted NGS leads to the identification of a novel homozygous nonsense mutation c.2217G > A, p.(Trp739*) in the exon 16 of LAMA2. Sanger sequencing confirmed this mutation in the affected patient and showed that her parents are heterozygous carriers.

Conclusions

A modern genetic analysis by NGS improves the genetic diagnosis pathway for adequate genetic counseling of affected families more precisely. An accession number from the National Center for Biotechnology Information (NCBI) ClinVar database was retrieved for this novel LAMA2 mutation.
Small-volume detection: platform developments for clinically-relevant applications
Authors: Sung Wei-Hsuan , Tsao Yu-Ting , Shen Ching-Ju , Tsai Chia-Ying , Cheng Chao-Min
Published: April 2021

Biochemical analysis of human body fluids is a frequent and fruitful strategy for disease diagnosis. Point-of-care (POC) diagnostics offers the tantalizing possibility of providing rapid diagnostic results in non-laboratory settings. Successful diagnostic testing using body fluids has been reported on in the literature; however, small-volume detection devices, which offer remarkable advantages such as portability, inexpensiveness, capacity for mass production, and tiny sample volume requirements have not been thoroughly discussed. Here, we review progress in this research field, with a focus on developments since 2015. In this review article, we provide a summary of articles that have detailed the development of small-volume detection strategies using clinical samples over the course of the last 5 years. Topics covered include small-volume detection strategies in ophthalmology, dermatology or plastic surgery, otolaryngology, and cerebrospinal fluid analysis. In ophthalmology, advances in technology could be applied to examine tear or anterior chamber (AC) fluid for glucose, lactoferrin, interferon, or VEGF. These approaches could impact detection and care for diseases including diabetic mellitus, dry-eye disease, and age-related maculopathy. Early detection and easy monitoring are critical approaches for improving overall care and outcome. In dermatology or plastic surgery, small-volume detection strategies have been applied for passive or interactive wound dressing, wound healing monitoring, and blister fluid analysis for autoimmune disease diagnosis. In otolaryngology, the analysis of nasal secretions and mucosa could be used to differentiate between allergic responses and infectious diseases. Cerebrospinal fluid analysis could be applied in neurodegenerative diseases, central neural system infection and tumor diagnosis. Other small-volume fluids that have been analyzed for diagnostic and monitoring purposes include semen and cervico-vaginal fluids. We include more details regarding each of these fluids, associated collection and detection devices, and approaches in our review.
Regulatory standards and processes for over-the-counter availability of hormonal contraception and drugs for medical abortion in five countries in the Eastern Mediterranean Region
Authors: Ammerdorffer Anne , Laws Mark , Awiligwe Arinze , Erb Florence , Im-Amornphong Wallada , Gülmezoglu A. Metin , Chinery Lester , Lucido Briana , Narasimhan Manjulaa
Published: April 2021

The World Health Organization 2019 WHO consolidated guideline on self-care interventions for health: sexual and reproductive health and rights includes recommendations on self-administration of injectable contraception, over-the-counter (OTC) oral contraception and self-management of medical abortion. A review of the regulatory status of these two self-care interventions can highlight processes required to ensure that the quality of the medicines and safety of individuals are safeguarded in the introduction and scale-up in countries. This review outlines the legal regulatory status of prescription-only medicine (POM) and OTC contraceptives, including emergency contraception, and drugs for medical abortion in Egypt, Jordan, Lebanon, Morocco and Tunisia using information obtained from internet searches, regulatory information databases and personal contacts. In addition, the review examines whether the national medicines regulatory authorities have documented procedures available to allow for a change in status from a POM to OTC to allow for increased accessibility, availability and uptake of self-care interventions recommended by WHO. Egypt, Jordan and Lebanon have a documented national OTC list available. The only contraceptive product mentioned in the OTC lists across all five countries is ellaOne (ulipristal acetate for emergency contraception), which is publicly registered in Lebanon. None of the five countries has an official documented procedure to apply for the change of POM to OTC. Informal procedures exist, such as the ability to apply to the national medicines regulatory authority for OTC status if the product has OTC status in the original country of manufacture. However, many of these procedures are not officially documented, highlighting the need for establishing sound, affordable and effective regulation of medical products as an important part of health system strengthening. From a public health perspective, it would be advantageous for licensed products to be available OTC. This is particularly the case for settings where the health system is under-resourced or over-stretched due to health emergencies. Readiness of national regulatory guidelines and OTC procedures could lead to increased access, availability and usage of essential self-care interventions for sexual and reproductive health and rights.
Community-led HIV self-testing for men who have sex with men in Lebanon: lessons learned and impact of COVID-19
Authors: Maatouk Ismael , Nakib Mostafa El , Assi Moubadda , Farah Patrick , Makso Bertho , Nakib Clara El , Rady Alissar
Published: April 2021

Background

In Lebanon, HIV is concentrated in both native and refugee communities of men who have sex with men (MSM). For over 10 years, the National AIDS Program (NAP) has offered HIV voluntary counselling and testing through a partnership with nongovernmental organizations (NGOs). In 2018, implementation of HIV self-tests (HIVST) was introduced, and this self-care intervention has been further scaled up during the coronavirus disease 2019 (COVID-19) pandemic. This paper (1) describes the effectiveness of implementing HIVST in Lebanon, and (2) discusses how the success of HIVST implementation has been reflected during the COVID-19 pandemic.

Methods

The NAP conducted a series of workshops (July–November 2018) to introduce HIVST services for healthcare workers working at different NGOs. The workshops highlighted that HIVST would be distributed for free, that it would be confidential and voluntary, and that participants were encouraged to notify the NGOs of their results, which would be kept strictly confidential. NGOs collected data anonymously and confidentially from beneficiaries (age, consistency of condom use and HIV testing history), who were asked to call back with the results of their HIVST. At the NAP, data were combined, aggregated and analysed.

Results

In 2019, the NGOs distributed 1103/1380 (79.9%) HIVST kits to their beneficiaries. The NGOs collected feedback on 111 kit results, of which two were HIV-positive. Feedback about HIVST results from beneficiaries was low (111/1103) due to noncompliance of beneficiaries and the lack of human and financial resources in the NGOs. From January through May 2020, a total of 625/780 HIVST kits (80.1%) were distributed. This period was divided into pre-COVID-19 and during COVID-19. The follow-up with the beneficiaries during COVID-19 was much improved because of the absence of on-site activities, shifting more efforts towards HIVST (449/625). There have been no reports of social harm related to HIVST.

Conclusion

HIVST implementation in Lebanon serves as an example of introducing a self-care intervention as part of a community-led effort. In order to maintain HIVST services at the same improved level, reorganization of care is needed within each NGO following the adaptation process due to COVID-19, along with continuous monitoring and evaluation of HIVST reported data.
Protein phosphatases in TLR signaling
Authors: Seumen Clovis H. T. , Grimm Tanja M. , Hauck Christof R.
Published: April 2021

Toll-like receptors (TLRs) are critical sensors for the detection of potentially harmful microbes. They are instrumental in initiating innate and adaptive immune responses against pathogenic organisms. However, exaggerated activation of TLR receptor signaling can also be responsible for the onset of autoimmune and inflammatory diseases. While positive regulators of TLR signaling, such as protein serine/threonine kinases, have been studied intensively, only little is known about phosphatases, which counterbalance and limit TLR signaling. In this review, we summarize protein phosphorylation events and their roles in the TLR pathway and highlight the involvement of protein phosphatases as negative regulators at specific steps along the TLR-initiated signaling cascade. Then, we focus on individual phosphatase families, specify the function of individual enzymes in TLR signaling in more detail and give perspectives for future research. A better understanding of phosphatase-mediated regulation of TLR signaling could provide novel access points to mitigate excessive immune activation and to modulate innate immune signaling.
Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Authors: Wirth Klaus J. , Scheibenbogen Carmen
Published: April 2021

Chronic Fatigue Syndrome or Myalgic Encephaloymelitis (ME/CFS) is a frequent debilitating disease with an enigmatic etiology. The finding of autoantibodies against ß2-adrenergic receptors (ß2AdR) prompted us to hypothesize that ß2AdR dysfunction is of critical importance in the pathophysiology of ME/CFS. Our hypothesis published previously considers ME/CFS as a disease caused by a dysfunctional autonomic nervous system (ANS) system: sympathetic overactivity in the presence of vascular dysregulation by ß2AdR dysfunction causes predominance of vasoconstrictor influences in brain and skeletal muscles, which in the latter is opposed by the metabolically stimulated release of endogenous vasodilators (functional sympatholysis). An enigmatic bioenergetic disturbance in skeletal muscle strongly contributes to this release. Excessive generation of these vasodilators with algesic properties and spillover into the systemic circulation could explain hypovolemia, suppression of renin (paradoxon) and the enigmatic symptoms. In this hypothesis paper the mechanisms underlying the energetic disturbance in muscles will be explained and merged with the first hypothesis. The key information is that ß2AdR also stimulates the Na+/K+-ATPase in skeletal muscles. Appropriate muscular perfusion as well as function of the Na+/K+-ATPase determine muscle fatigability. We presume that dysfunction of the ß2AdR also leads to an insufficient stimulation of the Na+/K+-ATPase causing sodium overload which reverses the transport direction of the sodium-calcium exchanger (NCX) to import calcium instead of exporting it as is also known from the ischemia–reperfusion paradigm. The ensuing calcium overload affects the mitochondria, cytoplasmatic metabolism and the endothelium which further worsens the energetic situation (vicious circle) to explain postexertional malaise, exercise intolerance and chronification. Reduced Na+/K+-ATPase activity is not the only cause for cellular sodium loading. In poor energetic situations increased proton production raises intracellular sodium via sodium-proton-exchanger subtype-1 (NHE1), the most important proton-extruder in skeletal muscle. Finally, sodium overload is due to diminished sodium outward transport and enhanced cellular sodium loading. As soon as this disturbance would have occurred in a severe manner the threshold for re-induction would be strongly lowered, mainly due to an upregulated NHE1, so that it could repeat at low levels of exercise, even by activities of everyday life, re-inducing mitochondrial, metabolic and vascular dysfunction to perpetuate the disease.
Utilization of wearable technology to assess gait and mobility post-stroke: a systematic review
Authors: Peters Denise M. , O’Brien Emma S. , Kamrud Kira E. , Roberts Shawn M. , Rooney Talia A. , Thibodeau Kristen P. , Balakrishnan Swapna , Gell Nancy , Mohapatra Sambit
Published: April 2021

Background

Extremity weakness, fatigue, and postural instability often contribute to mobility deficits in persons after stroke. Wearable technologies are increasingly being utilized to track many health-related parameters across different patient populations. The purpose of this systematic review was to identify how wearable technologies have been used over the past decade to assess gait and mobility in persons with stroke.

Methods

We performed a systematic search of Ovid MEDLINE, CINAHL, and Cochrane databases using select keywords. We identified a total of 354 articles, and 13 met inclusion/exclusion criteria. Included studies were quality assessed and data extracted included participant demographics, type of wearable technology utilized, gait parameters assessed, and reliability and validity metrics.

Results

The majority of studies were performed in either hospital-based or inpatient settings. Accelerometers, activity monitors, and pressure sensors were the most commonly used wearable technologies to assess gait and mobility post-stroke. Among these devices, spatiotemporal parameters of gait that were most widely assessed were gait speed and cadence, and the most common mobility measures included step count and duration of activity. Only 4 studies reported on wearable technology validity and reliability metrics, with mixed results.

Conclusion

The use of various wearable technologies has enabled researchers and clinicians to monitor patients’ activity in a multitude of settings post-stroke. Using data from wearables may provide clinicians with insights into their patients’ lived-experiences and enrich their evaluations and plans of care. However, more studies are needed to examine the impact of stroke on community mobility and to improve the accuracy of these devices for gait and mobility assessments amongst persons with altered gait post-stroke.
Sex differences in association between cognitive impairment and clinical correlates in Chinese patients with first-episode drug-naïve schizophrenia
Authors: Zhao Na , Wang Xiao Hong , Kang Chuan Yi , Zheng Yue , Yang Li Ying , Guan Tie Feng , Bai Yun Xia , Wei Ran , Hinman Hunter C. , Zhang Xiang Yang
Published: April 2021

Background

Schizophrenia is a complex mental illness with significant sex differences. Cognitive impairment is common in patients with schizophrenia, even in remission. This study was designed to examine the sex differences in the relationship between cognitive impairment and clinical correlations with first-episode drug-naïve (FEDN) schizophrenia.

Methods

93 FEDN patients (male/female = 45/48) and 160 controls (male/female = 74/86) were enrolled to compare the sex differences in cognitive functions measured by the MATRICS Consensus Cognitive Battery (MCCB). Positive and Negative Syndrome Scale (PANSS) and Hamilton Depression Scale (HAMD) were used to evaluate patients' clinical symptoms. We compared cognitive impairment with sociodemographic characteristics and measures of different genders, as well as group-by-sex interactions.

Results

Our results showed that male patients had significantly lower scores for symbol coding, digital sequence, and verbal learning than female patients, while the healthy controls showed similar sex differences. In female patients, multiple linear regression analysis confirmed that PANSS negative symptoms and general psychopathology scores, HAMD total score, and education level were independent contributors to MCCB total score. In male patients, only education was an independent contributor to MCCB total score.

Conclusions

These findings revealed significant sex differences in cognitive impairments and clinical symptoms in FEDN, which will be worthy of a follow-up study of schizophrenia in the future.
Development and validation of a nomogram predicting the risk of recurrent lumbar disk herniation within 6 months after percutaneous endoscopic lumbar discectomy
Authors: Jia Mengxian , Sheng Yadong , Chen Guoliang , Zhang Wenbin , Lin Jiajin , Lu Sheng , Li Fayi , Ying Jinwei , Teng Honglin
Published: April 2021

Objective

To develop and validate a nomogram useful in predicting recurrent lumbar disk herniation (rLDH) within 6 months after percutaneous endoscopic lumbar discectomy (PELD).

Methods

Information on patients’ lumbar disk herniation (LDH) between January 2018 and May 2019 in addition to 26 other features was collected from the authors’ hospital. The least absolute shrinkage and selection operator (LASSO) method was used to select the most important risk factors. Moreover, a nomogram was used to build a prediction model using the risk factors selected from LASSO regression. The concordance index (C-index), the receiver operating characteristic (ROC) curve, and calibration curve were used to assess the performance of the model. Finally, clinical usefulness of the nomogram was analyzed using the decision curve and bootstrapping used for internal validation.

Results

Totally, 352 LDH patients were included into this study. Thirty-two patients had recurrence within 6 months while 320 showed no recurrence. Four potential factors, the course of disease, Pfirrmann grade, Modic change, and migration grade, were selected according to the LASSO regression model. Additionally, the C-index of the prediction nomogram was 0.813 (95% CI, 0.726-0.900) and the area under receiver operating characteristic curve (AUC) value was 0.798 while the interval bootstrapping validation C-index was 0.743. Hence, the nomogram might be a good predictive model.

Conclusion

Each variable, the course of disease, Pfirrmann grade, Modic change, and migration grade in the nomogram had a quantitatively corresponding risk score, which can be used in predicting the overall recurrence rate of rLDH within 6 months.
Diagnostic delays in vasculitis and factors associated with time to diagnosis
Authors:   for the Vasculitis Patient-Powered Research Network, Sreih Antoine G. , Cronin Keri , Shaw Dianne G. , Young Kalen , Burroughs Cristina , Kullman Joyce , Machireddy Kirthi , McAlear Carol A. , Merkel Peter A.
Published: April 2021

Background

Patients with vasculitis, a set of rare diseases, encounter delays in obtaining an accurate diagnosis which can lead to substantial morbidity and increased mortality. This study sought to describe the diagnostic journey of patients with vasculitis and identify factors associated with time to diagnosis.

Methods

Patients with vasculitis enrolled in an online registry completed a two-stage study: Stage 1: survey of open-ended questions about patients’ diagnostic journeys and perceived factors associated with rapid or delayed diagnosis; Stage 2: survey with specific questions based on data from Stage 1 and additional investigator-identified factors.

Results

375 patients with vasculitis participated in Stage 1; 456 patients participated in Stage 2. 85% of patients were seen by a healthcare provider within 3 months of the onset of symptoms. The median time to diagnosis of vasculitis was 7 months. 313/456 (73%) of patients were misdiagnosed initially. 40% of diagnoses were made in a hospital setting; 2% of diagnoses were made at a specialized vasculitis center. 60% of patients had at least 1 visit to an emergency room prior to diagnosis. Unemployment, time to travel to a medical center > 1 h, initial misdiagnosis, and delays in seeing a specialist were all associated with longer times to diagnosis. 373/456 (82%) of patients reported that a delayed diagnosis had negative consequences on their health.

Conclusion

Patients with vasculitis encounter substantial delays in achieving an accurate diagnosis and these delays are associated with negative health consequences. Both patient-related factors and healthcare-related factors are associated with diagnostic delays.
Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors in clinical trials for cancer immunotherapy
Authors: Tang Kai , Wu Ya-Hong , Song Yihui , Yu Bin
Published: April 2021

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme enzyme that catalyzes the oxidation of L-tryptophan. Functionally, IDO1 has played a pivotal role in cancer immune escape via catalyzing the initial step of the kynurenine pathway, and overexpression of IDO1 is also associated with poor prognosis in various cancers. Currently, several small-molecule candidates and peptide vaccines are currently being assessed in clinical trials. Furthermore, the “proteolysis targeting chimera” (PROTAC) technology has also been successfully used in the development of IDO1 degraders, providing novel therapeutics for cancers. Herein, we review the biological functions of IDO1, structural biology and also extensively summarize medicinal chemistry strategies for the development of IDO1 inhibitors in clinical trials. The emerging PROTAC-based IDO1 degraders are also highlighted. This review may provide a comprehensive and updated overview on IDO1 inhibitors and their therapeutic potentials.
Prescribing patterns, indications and adverse events of ibuprofen in children: results from a national survey among Italian pediatricians
Authors: Martinelli Massimo , Quaglietta Lucia , Banderali Giuseppe , Ferrara Pietro , Romano Claudio , Staiano Annamaria
Published: April 2021

Background

Despite ibuprofen widely recognized safety profile, an increase of suspected adverse events has been reported in the last decade in parallel with its growing over-the-counter use. The aims of this study were to assess the therapeutic approach to the feverish child and to evaluate the main indications and the most frequent adverse events related to ibuprofen administration in children.

Methods

A specific questionnaire-form regarding the management of ibuprofen therapy in children was distributed among a sample of pediatricians all over the Italian territory between September and October 2020. An electronic data collection through a specifically designed web-based platform was performed among the participating pediatricians.

Results

One-hundred-eighty-one pediatricians completed the survey. In case of fever, 177 (98%) participants prescribe paracetamol, while only 4 (2%) preferred ibuprofen as first choice. One-hundred-twenty-eight pediatricians (71%) administer paracetamol alone, while 53 (29.2%) use the combined/alternating treatment with ibuprofen. Ibuprofen is mostly administered for musculoskeletal pain (30%), upper respiratory tract infection (20%), headache (15%) and post-surgical pain (9%). Sixty-three (35%) out of 181 participating pediatricians reported 191 adverse events during ibuprofen administration. The most common were gastrointestinal (GI), with GI bleeding being reported in 30/191 cases (15.7%), epigastric pain in 29/191 (15.1%), non-specified abdominal pain in 22/191 (11.1%) and nausea/vomiting in 21/191 (11%). Severe adverse events including kidney damage (3.1%), complicated infections (0.5%), pneumonia associated empyema (0.5%), soft tissue infection (0.5%) and disseminated intravascular coagulation (0.5%) were also reported. The adverse events led to a hospitalization in 12% of children. In 53/191 cases (28%) the adverse events were related to a wrong dosage or prolonged therapy or errors in frequency of administration.

Conclusions

This survey demonstrate a sufficient awareness of Italian pediatricians regarding ibuprofen-prescribing patterns with the only possible concern related to the relatively high percentage of pediatricians performing a combining/alternating use of paracetamol and ibuprofen. The reported adverse events were mild in most of the cases and often related to errors in dosage, frequency and treatment duration, emphasizing the need for a major caution of both practitioners and patients in their use.
Further engineering of R. toruloides for the production of terpenes from lignocellulosic biomass
Authors: Kirby James , Geiselman Gina M. , Yaegashi Junko , Kim Joonhoon , Zhuang Xun , Tran-Gyamfi Mary Bao , Prahl Jan-Philip , Sundstrom Eric R. , Gao Yuqian , Munoz Nathalie , Burnum-Johnson Kristin E. , Benites Veronica T. , Baidoo Edward E. K. , Fuhrmann Anna , Seibel Katharina , Webb-Robertson Bobbie-Jo M. , Zucker Jeremy , Nicora Carrie D. , Tanjore Deepti , Magnuson Jon K. , Skerker Jeffrey M. , Gladden John M.
Published: April 2021

Background

Mitigation of climate change requires that new routes for the production of fuels and chemicals be as oil-independent as possible. The microbial conversion of lignocellulosic feedstocks into terpene-based biofuels and bioproducts represents one such route. This work builds upon previous demonstrations that the single-celled carotenogenic basidiomycete, Rhodosporidium toruloides, is a promising host for the production of terpenes from lignocellulosic hydrolysates.

Results

This study focuses on the optimization of production of the monoterpene 1,8-cineole and the sesquiterpene α-bisabolene in R. toruloides. The α-bisabolene titer attained in R. toruloides was found to be proportional to the copy number of the bisabolene synthase (BIS) expression cassette, which in turn influenced the expression level of several native mevalonate pathway genes. The addition of more copies of BIS under a stronger promoter resulted in production of α-bisabolene at 2.2 g/L from lignocellulosic hydrolysate in a 2-L fermenter. Production of 1,8-cineole was found to be limited by availability of the precursor geranylgeranyl pyrophosphate (GPP) and expression of an appropriate GPP synthase increased the monoterpene titer fourfold to 143 mg/L at bench scale. Targeted mevalonate pathway metabolite analysis suggested that 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGR), mevalonate kinase (MK) and phosphomevalonate kinase (PMK) may be pathway bottlenecks are were therefore selected as targets for overexpression. Expression of HMGR, MK, and PMK orthologs and growth in an optimized lignocellulosic hydrolysate medium increased the 1,8-cineole titer an additional tenfold to 1.4 g/L. Expression of the same mevalonate pathway genes did not have as large an impact on α-bisabolene production, although the final titer was higher at 2.6 g/L. Furthermore, mevalonate pathway intermediates accumulated in the mevalonate-engineered strains, suggesting room for further improvement.

Conclusions

This work brings R. toruloides closer to being able to make industrially relevant quantities of terpene from lignocellulosic biomass.
Correction to: Aedes larval bionomics and implications for dengue control in the paradigmatic Jafna peninsula, northern Sri Lanka
Authors: Surendran Sinnathamby N. , Jayadas Tibutius T. P. , Thiruchenthooran Vaikunthavasan , Raveendran Selvarajah , Tharsan Annathurai , Santhirasegaram Sharanga , Sivabalakrishnan Kokila , Karunakaran Suthakar , Ponnaiah Bharathy , Gomes Laksiri , Malavige Gathsaurie N. , Ramasamy Ranjan
Published: April 2021

An amendment to this paper has been published and can be accessed via the original article.
Human and animal cystic echinococcosis in Tataouine governorate: hypoendemic area in a hyperendemic country, myth or reality?
Authors: M’rad Selim , Chaâbane-Banaoues Raja , Ghrab Massaouda , Babba Hamouda , Oudni-M’rad Myriam
Published: April 2021

Background

Cystic echinococcosis (CE) has a worldwide distribution and is especially prevalent in North African countries. With a mean annual surgical incidence (ASI) of CE of 12.7 per 100,000 inhabitants, Tunisia is one of the most CE endemic countries in the Mediterranean area. Tataouine governorate is considered to be the most CE hypoendemic region in Tunisia (ASI = 0.92) despite favourable socioeconomic conditions that enable maintenance of the Echinococcus granulosussensu lato (s.l.) life-cycle and a significant environmental contamination with E. granulosuss.l. eggs. The aim of this study was to assess human CE seroprevalence, prevalence of CE in food animals and environmental contamination by E. granulosus s.l. eggs in different districts of Tataouine governorate.

Methods

This study was conducted from January to December 2018. A total of 374 human sera samples were tested for the presence of immunoglobulin G antibodies against E. granulosus using a commercial ELISA kit. Specimens were also collected from animals slaughtered at the Tataouine abattoir (n = 8609) and examined for the presence of hydatid cysts; 111 hydatid cysts were genotyped. Eggs of E. granulosuss.l. were identified by PCR and DNA sequencing from dog faecal samples (n = 288).

Results

Serological tests showed that 8.5% of the sera samples tested were positive for E. granulosus-specific antibodies. The average prevalence of hydatidosis in livestock was 1.6%, and CE infection was more prevalent in cattle than in sheep, goats and dromedaries. The contamination rate of dog faeces by E. granulosus sensu stricto eggs varied significantly from 0 to 23.5% depending on the collection area. Molecular analyses only revealed the presence of the G1 genotype for cysts and eggs.

Conclusions

Based on our findings, CE is likely to be more endemic in the Tataouine governorate than previously described. Thus, to implement an effective control programme against CE, a national survey should be carried out to determine human CE prevalence in the different Tunisian governorates.

Graphical Abstract
Epitranscriptomic profile of Lactobacillus agilis and its adaptation to growth on inulin
Authors: Wang Hongzhou , Simpson Jennifer H. , Kotra Madison E. , Zhu Yuanting , Wickramasinghe Saumya , Mills David A. , Chiu Norman H. L.
Published: April 2021

Objective

Ribonucleic acids (RNA) are involved in many cellular functions. In general, RNA is made up by only four different ribonucleotides. The modifications of RNA (epitranscriptome) can greatly enhance the structural diversity of RNA, which in turn support some of the RNA functions. To determine whether the epitranscriptome of a specific probiotic is associated with its adaptation to the source of energy, Lactobacillus agilis (YZ050) was selected as a model and its epitranscriptome was profiled and compared by using mass spectrometry.

Results

The L. agilis epitranscriptome (minus rRNA modifications) consists of 17 different RNA modifications. By capturing the L. agilis cells during exponential growth, reproducible profiling was achieved. In a comparative study, the standard source of energy (glucose) in the medium was substituted by a prebiotic inulin, and a downward trend in the L. agilis epitranscriptome was detected. This marks the first report on a system-wide variation of a bacterial epitranscriptome that resulted from adapting to an alternative energy source. No correlation was found between the down-regulated RNA modifications and the expression level of corresponding writer genes. Whereas, the expression level of a specific exonuclease gene, RNase J1, was detected to be higher in cells grown on inulin.
DNA methylation biomarkers of myocardial infarction and cardiovascular disease
Authors: Fernández-Sanlés Alba , Sayols-Baixeras Sergi , Subirana Isaac , Sentí Mariano , Pérez-Fernández S. , de Castro Moura Manuel , Esteller Manel , Marrugat Jaume , Elosua Roberto
Published: April 2021

Background

The epigenetic landscape underlying cardiovascular disease (CVD) is not completely understood and the clinical value of the identified biomarkers is still limited. We aimed to identify differentially methylated loci associated with acute myocardial infarction (AMI) and assess their validity as predictive and causal biomarkers.

Results

We designed a case–control, two-stage, epigenome-wide association study on AMI (ndiscovery = 391, nvalidation = 204). DNA methylation was assessed using the Infinium MethylationEPIC BeadChip. We performed a fixed-effects meta-analysis of the two samples. 34 CpGs were associated with AMI. Only 12 of them were available in two independent cohort studies (n ~ 1800 and n ~ 2500) with incident coronary and cardiovascular disease (CHD and CVD, respectively). The Infinium HumanMethylation450 BeadChip was used in those two studies. Four of the 12 CpGs were validated in association with incident CHD: AHRR-mapping cg05575921, PTCD2-mapping cg25769469, intergenic cg21566642 and MPO-mapping cg04988978. We then assessed whether methylation risk scores based on those CpGs improved the predictive capacity of the Framingham risk function, but they did not. Finally, we aimed to study the causality of those associations using a Mendelian randomization approach but only one of the CpGs had a genetic influence and therefore the results were not conclusive.

Conclusions

We have identified 34 CpGs related to AMI. These loci highlight the relevance of smoking, lipid metabolism, and inflammation in the biological mechanisms related to AMI. Four were additionally associated with incident CHD and CVD but did not provide additional predictive information.