bluuebunny/crossref_metadata_2025 huggingface dataset:
RAMS11 promotes CRC through mTOR-dependent inhibition of autophagy, suppression of apoptosis, and promotion of epithelial-mesenchymal transition
Authors: Islam Khan Md Zahirul , Law Helen Ka Wai
Published: June 2021

Background

Long non-coding RNAs (lncRNAs), a class of non-coding RNAs (ncRNAs) associated with diverse biological processes of cells. Over the past decades, cumulating research evidences revealed that abnormal expressions of lncRNAs are associated with colorectal cancer (CRC) initiation, progression, metastasis, and resistance to therapies. Moreover, their usefulness as candidate biomarkers for CRC diagnosis and prognosis are well evident throughout previous literature. In the current study, we examined the role and molecular mechanisms of newly identified lncRNA named RNA associated with metastasis-11 (RAMS11) in CRC development.

Methods

The expression of RAMS11 in CRC cell lines DLD-1, HT-29, HCT-116, and SW480 and colon normal cells CCD-112-CoN were evaluated by quantitative RT-qPCR. The results showed that the RAMS11 is significantly upregulated in CRC cell lines compared to the normal cells. The CCK-8 proliferation assay, colony formation assay, and migration assay were performed to evaluate the biological and physiological functions of RAMS11 in vitro. To decipher the molecular mechanisms of RAMS11 medicated CRC progression, we further performed western blot analysis of the key pathway proteins (e.g., AMPK, AKT, and mTOR).

Results

Our results revealed that higher expression of RAMS11 is associated with increased CRC proliferation, migration, and development of metastasis. Knockdown of RAMS11 induced autophagy, apoptosis along with reduction of epithelial-mesenchymal transition (EMT) suggesting that RAMS11 is involved in CRC progression. The molecular mechanisms of RAMS11 indicated that knockdown of RAMS11 significantly inhibited CRC carcinogenesis through mTOR-dependent autophagy induction.

Conclusions

In sum, our results suggested that RAMS11 is an important oncogene in CRC pathogenesis. Targeting RAMS11 could be a potential therapeutic strategy for CRC management.
Challenges and opportunities for use of long-lasting insecticidal nets to prevent malaria during overnight travel in Uganda: a qualitative study
Authors: Ekusai-Sebatta Deborah , Arinaitwe Emmanuel , Mpimbaza Arthur , Nankabirwa Joaniter I. , Drakeley Chris , Rosenthal Philip J. , Staedke Sarah G. , Muyinda Herbert
Published: June 2021

Background

Travel is a well-recognized risk factor for malaria. Within sub-Saharan Africa, travellers from areas of lower to higher transmission intensity are potentially at high risk of malaria. Long-lasting insecticidal nets (LLINs) are the primary tool for prevention of malaria, and their widespread use has contributed to substantial reductions in malaria burden. However, travellers often fail to use LLINs. To further explore the challenges and opportunities of using LLINs, travellers were interviewed in Uganda.

Methods

In August and September 2019, 20 participants attending outpatient clinics at Naguru General Hospital in Kampala with a history of travel out of Kampala within the previous 60 days were purposively selected. Data were collected through in-depth interviews and analysed thematically using NVivo 12.

Results

Of the 20 participants, 13 were male. Thirteen of the 20 participants tested positive for malaria by microscopy, and 5 reported using of LLINs during travel. The main reasons for travel were to attend social events (weddings, funerals, overnight prayers) and for work. travellers who attended social events reported using LLINs less commonly than those who travelled for work. Challenges to using LLINs during travel included: (1) limited access to LLINs; (2) challenges in planning ahead of travel; (3) lack of space or ability to hang LLINs while travelling; (4) impression that LLINs in lodging places were unhygienic; (5) cultural beliefs discouraging use of LLINs during social events; (6) participation in overnight ceremonies; and (7) doubts about efficacy of LLINs. Positive factors influencing use of LLINs during travel included knowledge regarding malaria prevention and good affordability and availability of LLINs.

Conclusions

Despite good traveller knowledge regarding malaria control measures, use of LLINs was limited. Use of LLINs in the prevention of malaria among travellers from low to high transmission settings needs to be prioritized. This calls for increased behaviour change oriented communication to improve traveller preparedness and consideration of use of repellents in situations where LLINs may not be feasible. The Uganda Ministry of Health and Malaria Control Division should use educational messages to increase awareness about the risks of getting malaria during overnight travel through the media. Truck drivers should be sensitized through their companies to use the available space at the back of the trucks for hanging nets and consider using pop-up nets.
Transient knockdown of Anopheles stephensi LRIM1 using RNAi increases Plasmodium falciparum sporozoite salivary gland infections
Authors: Billingsley Peter F. , George Kasim I. , Eappen Abraham G. , Harrell Robert A. , Alford Robert , Li Tao , Chakravarty Sumana , Sim B. Kim Lee , Hoffman Stephen L. , O’Brochta David A.
Published: June 2021

Background

Plasmodium falciparum(Pf) sporozoites (PfSPZ) can be administered as a highly protective vaccine conferring the highest protection seen to date. Sanaria® PfSPZ vaccines are produced using aseptically rearedAnopheles stephensimosquitoes. The bionomics of sporogonic development ofP. falciparuminA. stephensito fully mature salivary gland PfSPZ is thought to be modulated by several components of the mosquito innate immune system. In order to increase salivary gland PfSPZ infections inA. stephensiand thereby increase vaccine production efficiency, a gene knock down approach was used to investigate the activity of the immune deficiency (IMD) signaling pathway downstream effector leucine-rich repeat immune molecule 1 (LRIM1), an antagonist toPlasmodiumdevelopment.

Methods

Expression ofLRIM1inA. stephensiwas reduced following injection of double stranded (ds) RNA into mosquitoes. By combining the Gal4/UAS bipartite system with in vivo expression of short hairpin (sh) RNA coding forLRIM1reduced expression ofLRIM1was targeted in the midgut, fat body, and salivary glands. RT-qPCR was used to demonstrate fold-changes in gene expression in three transgenic crosses and the effects onP. falciparuminfections determined in mosquitoes showing the greatest reduction inLRIM1expression.

Results

LRIM1expression could be reduced, but not completely silenced, by expression ofLRIM1dsRNA. Infections ofP. falciparumoocysts and PfSPZ were consistently and significantly higher in transgenic mosquitoes than wild type controls, with increases in PfSPZ ranging from 2.5- to tenfold.

Conclusions

Plasmodium falciparuminfections inA. stephensican be increased following reduced expression ofLRIM1.These data provide the springboard for more precise knockout of LRIM1 for the eventual incorporation of immune-compromisedA. stephensiinto manufacturing of Sanaria’s PfSPZ products.
The malaria burden of Amerindian groups of three Venezuelan states: a descriptive study based on programmatic data
Authors: Gabaldón-Figueira Juan C. , Chaccour Carlos , Moreno Jorge , Villegas Maria , Villegas Leopoldo
Published: June 2021

Background

Fifty-three percent of all cases of malaria in the Americas in 2019 came from Venezuela, where the epidemic is heavily focused south of the Orinoco river, and where most of the country’s Amerindian groups live. Although the disease is known to represent a significant public health problem among these populations, little epidemiological data exists on the subject. This study aims to provide information on malaria incidence, geospatial clustering, and risk factors associated to Plasmodium falciparum infection among these groups.

Methods

This is a descriptive study based on the analysis of published and unpublished programmatic data collected by Venezuelan health authorities and non-government organizations between 2014 and 2018. The Annual Parasite Index among indigenous groups (API-i) in municipalities of three states (Amazonas, Bolivar, and Sucre) were calculated and compared using the Kruskal Wallis test, risk factors for Plasmodium falciparum infection were identified via binomial logistic regression and maps were constructed to identify clusters of malaria cases among indigenous patients via Moran’s I and Getis-Ord’s hot spot analysis.

Results

116,097 cases of malaria in Amerindian groups were registered during the study period. An increasing trend was observed between 2014 and 2016 but reverted in 2018. Malaria incidence remains higher than in 2014 and hot spots were identified in the three states, although more importantly in the south of Bolivar. Most cases (73.3%) were caused by Plasmodium vivax, but the Hoti, Yanomami, and Eñepa indigenous groups presented higher odds for infection with Plasmodium falciparum.

Conclusion

Malaria cases among Amerindian populations increased between 2014 and 2018 and seem to have a different geographic distribution than those among the general population. These findings suggest that tailored interventions will be necessary to curb the impact of malaria transmission in these groups.
Rapid and precise diagnosis of pneumonia coinfected by Pneumocystis jirovecii and Aspergillus fumigatus assisted by next-generation sequencing in a patient with systemic lupus erythematosus: a case report
Authors: Chen Yili , Ai Lu , Zhou Yingqun , Zhao Yating , Huang Jianyu , Tang Wen , Liang Yujian
Published: June 2021

Background

Pneumocystis jirovecii and Aspergillus fumigatus, are opportunistic pathogenic fungus that has a major impact on mortality in patients with systemic lupus erythematosus. With the potential to invade multiple organs, early and accurate diagnosis is essential to the survival of SLE patients, establishing an early diagnosis of the infection, especially coinfection by Pneumocystis jirovecii and Aspergillus fumigatus, still remains a great challenge.

Case presentation

In this case, we reported that the application of next -generation sequencing in diagnosing Pneumocystis jirovecii and Aspergillus fumigatus coinfection in a Chinese girl with systemic lupus erythematosus (SLE). Voriconazole was used to treat pulmonary aspergillosis, besides sulfamethoxazole and trimethoprim (SMZ-TMP), and caspofungin acetate to treat Pneumocystis jirovecii infection for 6 days. On Day 10 of admission, her chest radiograph displayed obvious absorption of bilateral lung inflammation though the circumstance of repeated fever had not improved. Unfortunately, the patient discharged from the hospital since the financial burden, and during the follow-up, it was documented the patient died within one week after discharge.

Conclusions

This successful application of the next generation sequencing assisting the rapid diagnosis of Pneumocystis jirovecii and Aspergillus fumigatus coinfection provides a new perspective in the clinical approach against the systematic fungi infections and highlights the potential of this technique in rapid etiological diagnosis.
The association between family impact and health-related quality of life of children with idiopathic central precocious puberty in Chongqing, China
Authors: Yang Hong , Luo Shunqing , Liang Xiaohua , Lin Qin , Cheng Ting , Zeng Li , Tang Fang , Wu Di
Published: June 2021

Background

Idiopathic central precocious puberty (ICPP) reduces patient health-related quality of life (HRQoL). The impacts of disease and treatment on families are also an important concern. This study aimed to assess the association between family impact and HRQoL of children with ICPP.

Methods

We conducted a case–control study in Chongqing, China. A case group of 134 children with ICPP aged 5–12 years and their caregivers was recruited from a children’s hospital in Chongqing. A total of 210 gender- and age-matched subjects from two primary schools were selected as controls. PedsQLTM4.0 Generic Core Scales (GCS) and PedsQL™ Family Impact Module (FIM) were used in this study.

Results

Children with ICPP scored lower than controls in all HRQoL domains except physical functioning. In particular, the two groups were significantly different in emotional functioning scores (d = 0.414,P < 0.001). Compared with controls, ICPP families had lower scores in all dimensions of the FIM scale (d = 0.288–1.030, allP < 0.05). Factors associated with HRQoL of ICPP patients included: age of patients, type of medical treatment, employment status of caregivers, educational level of caregivers, parent HRQoL and family functioning (allP < 0.05).

Conclusions

Children with ICPP demonstrated lower quality of life and greater family impact compared to healthy controls. In addition, less impact of disease on parent HRQoL and family functioning was associated with better HRQoL of ICPP patients, patients aged older, treated with drug combination, cared by employed or well-educated caregivers reported better HRQoL. Health care professionals should pay more attention to younger patients treated with GnRHa alone, and provide targeted interventions for caregivers depending on their demographic background to reduce family impact and thereby improve patient HRQoL.
OTOGL, a gelforming mucin protein, is nonessential for male germ cell development and spermatogenesis in mice
Authors: Li Zhiming , Zhang Yan , Zhang Xinzong , Cao Congcong , Luo Xiaomin , Gui Yaoting , Tang Yunge , Yuan Shuiqiao
Published: June 2021

Otogelin-like protein (encoded by Otogl) was highly structural similar to the gelforming mucin proteins. Although human OTOG mutations have been linked to deafness, the biological function of OTOGL in male germ cell development remains enigmatic. In screening 336 patients with non-obstructive azoospermia (NOA), OTOGL displays the high mutant ratio (13.99 %). Then, we examined the expression of OTOGL in developing mouse testes. Otogl mRNA and protein are continually expressed in postnatal developing testes from postnatal day 0 (P0) testes to P21 testes exhibiting a decreased trend with the age growth. We thus generated a global Otogl knockout mouse (KO) model using the CRISPR/Cas9 technology; however, Otogl KO mice displayed normal development and fertility. Further histological analysis of Otogl knockout mouse testes revealed that all types of spermatogenic cells are present in Otogl KO seminiferous tubules. Together, our study suggested that OTOGL is nonessential for male germ cell development and spermatogenesis.
Predictive model based on gene and laboratory data for intravenous immunoglobulin resistance in Kawasaki disease in a Chinese population
Authors: Meng Li , Zhen Zhen , Jiang Qian , Li Xiao-hui , Yuan Yue , Yao Wei , Zhang Ming-ming , Li Ai-jie , Shi Lin
Published: June 2021

Background

Here, we investigated the predictive efficiency of a newly developed model based on single nucleotide polymorphisms (SNPs) and laboratory data for intravenous immunoglobulin (IVIG) resistance in Kawasaki disease (KD) in a Chinese population.

Methods

Data relating to children with KD were acquired from a single center between December 2015 and August 2019 and used to screen target SNPs. We then developed a predictive model of IVIG resistance using previous laboratory parameters. We then validated our model using data acquired from children with KD attending a second center between January and December 2019.

Results

Analysis showed that rs10056474 GG, rs746994GG, rs76863441GT, rs16944 (CT/TT), and rs1143627 (CT/CC), increased the risk of IVIG-resistance in KD patients (odds ratio, OR > 1). The new predictive model, which combined SNP data with a previous model derived from laboratory data, significantly increased the area under the receiver-operator-characteristic curves (AUC) (0.832, 95% CI: 0.776-0.878 vs 0.793, 95%CI:0.734-0.844, P < 0.05) in the development dataset, and (0.820, 95% CI: 0.730-0.889 vs 0.749, 95% CI: 0.652-0.830, P < 0.05) in the validation dataset. The sensitivity and specificity of the new assay were 65.33% (95% CI: 53.5-76.0%) and 86.67% (95% CI: 80.2-91.7%) in the development dataset and 77.14% (95% CI: 59.9-89.6%) and 86.15% (95% CI: 75.3-93.5%) in the validation dataset.

Conclusion

Analysis showed that rs10056474 and rs746994 in the SMAD5 gene, rs76863441 in the PLA2G7 gene, and rs16944 or rs1143627 in the interleukin (IL)-1B gene, were associated with IVIG resistant KD in a Chinese population. The new model combined SNPs with laboratory data and improved the predictve efficiency of IVIG-resistant KD.
Beyond the lesion site: minocycline augments inflammation and anxiety-like behavior following SCI in rats through action on the gut microbiota
Authors: Schmidt Emma K. A. , Raposo Pamela J. F. , Torres-Espin Abel , Fenrich Keith K. , Fouad Karim
Published: June 2021

Background

Minocycline is a clinically available synthetic tetracycline derivative with anti-inflammatory and antibiotic properties. The majority of studies show that minocycline can reduce tissue damage and improve functional recovery following central nervous system injuries, mainly attributed to the drug’s direct anti-inflammatory, anti-oxidative, and neuroprotective properties. Surprisingly the consequences of minocycline’s antibiotic (i.e., antibacterial) effects on the gut microbiota and systemic immune response after spinal cord injury have largely been ignored despite their links to changes in mental health and immune suppression.

Methods

Here, we sought to determine minocycline’s effect on spinal cord injury-induced changes in the microbiota-immune axis using a cervical contusion injury in female Lewis rats. We investigated a group that received minocycline following spinal cord injury (immediately after injury for 7 days), an untreated spinal cord injury group, an untreated uninjured group, and an uninjured group that received minocycline. Plasma levels of cytokines/chemokines and fecal microbiota composition (using 16s rRNA sequencing) were monitored for 4 weeks following spinal cord injury as measures of the microbiota-immune axis. Additionally, motor recovery and anxiety-like behavior were assessed throughout the study, and microglial activation was analyzed immediately rostral to, caudal to, and at the lesion epicenter.

Results

We found that minocycline had a profound acute effect on the microbiota diversity and composition, which was paralleled by the subsequent normalization of spinal cord injury-induced suppression of cytokines/chemokines. Importantly, gut dysbiosis following spinal cord injury has been linked to the development of anxiety-like behavior, which was also decreased by minocycline. Furthermore, although minocycline attenuated spinal cord injury-induced microglial activation, it did not affect the lesion size or promote measurable motor recovery.

Conclusion

We show that minocycline’s microbiota effects precede its long-term effects on systemic cytokines and chemokines following spinal cord injury. These results provide an exciting new target of minocycline as a therapeutic for central nervous system diseases and injuries.
Chlamydia trachomatis, Neisseria gonorrhoea, and Trichomonas vaginalis infections among pregnant women and male partners in Dutch midwifery practices: prevalence, risk factors, and perinatal outcomes
Authors: Op de Coul Eline L. M. , Peek Demi , van Weert Yolanda W. M. , Morré Servaas A. , Rours Ingrid , Hukkelhoven Chantal , de Jonge Ank , van Benthem Birgit , Pereboom Monique
Published: June 2021

Background

Antenatal screening for HIV, syphilis and HBV has been successfully implemented in The Netherlands, but data on other STI among pregnant women or male partners are limited. Our objectives: (i) to assess the prevalence of Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV) among pregnant women and male partners, (ii) to identify risk factors for these STI during pregnancy, and (iii) to identify adverse perinatal outcomes (APO) associated with STI.

Methods

Cross-sectional study. Pregnant women aged ≤ 30 years (n = 548) and male partners (n = 425) were included at 30 midwifery practices during 2012–2016. Participants provided a self-collected vaginal swab (women) or urine sample (men) and completed a questionnaire. Perinatal data were derived from pregnancy cards. APO was defined as premature rupture of membranes, preterm delivery, low birthweight, stillbirth, neonatal conjunctival and respiratory infections. Data were analysed by logistic regression.

Results

STI were present in 2.4% of pregnant women (CT 1.8%, NG 0.4%, TV 0.4%), and in 2.2% of male partners (CT 2.2%, NG 0.2%, TV 0%). Of young women (≤ 20 years), 12.5% had a CT infection. Prevalent STI during pregnancy was associated with female young age (≤ 20 years vs ≥ 21 years) (adjusted OR 6.52, CI 95%: 1.11–38.33), male non-Western vs Western background (aOR 9.34, CI 2.34–37.21), and female with ≥ 2 sex partners < 12 months vs 0–1 (aOR 9.88, CI 2.08–46.91). APO was not associated with STI, but was associated with female low education (aOR 3.36, CI 1.12–10.09), complications with previous newborn (aOR 10.49, CI 3.21–34.25 vs no complications) and short duration (0–4 years) of relationship (aOR 2.75, CI 1.41–5.39 vs ≥ 5 years). Small-for-gestational-age was not associated with STI, but was associated with female low education (aOR 7.81, 2.01–30.27), female non-Western background (aOR 4.41, 1.74–11.17), and both parents smoking during pregnancy (aOR 2.94, 1.01–8.84 vs both non-smoking).

Conclusions

Prevalence of STI was low among pregnant women and male partners in midwifery practices, except for CT among young women. The study could not confirm previously observed associations between STI and APO, which is probably due to low prevalence of STI, small study sample, and presumed treatment for STI.
Defining the optimal cut-point of self-reported ART adherence to achieve viral suppression in the era of contemporary HIV therapy: a cross-sectional study
Authors: O’Halloran Leach Emma , Lu Huiyin , Caballero Joshua , Thomas Jennifer E. , Spencer Emma C. , Cook Robert L.
Published: June 2021

Background

When considering adherence to antiretroviral therapy (ART) for HIV, many different cut-points are used. The primary goals of this study were to identify a level of self-reported medication adherence that best distinguished HIV viral suppression from non-suppression, and to compare the ability of a single-item and a 3-item adherence questionnaire to predict HIV viral suppression.

Methods

This cross-sectional analysis included 380 persons with HIV (PWH) from the Florida Cohort study who completed a self-reported ART adherence measure within 30-days of having an HIV viral load test. We used Receiver Operating Characteristic (ROC) curve analyses and ROCContrast to compare the ability of a single-item and a 3-item self-reported adherence measure to predict HIV viral suppression (defined as ≤ 200 copies/mL). We used the Youden index and chi square statistics to assess specific cut-points, and repeated the analysis with a different definition of HIV viral suppression (≤ 1000 copies/mL).

Results

The mean percent adherence was 92.4% using the single-item score and 90.4% using the 3-item score; 81.6% had viral suppression. The areas under the curve for the single-item and 3-item adherence measures were generally poor overall and not significantly different from each other (0.589 and 0.580, p = 0.67). The Youden index identified cut-points of 93% and 89% as maximizing the sensitivity and specificity for the single-item and 3-item measures, respectively, whereas a cut-point of 80% on the single-item measure was best able to discriminate those with viral suppression (58% vs. 84%, p < 0.001). Results were similar with viral suppression defined as ≤ 1000 copies/mL.

Conclusions

In this sample of PWH, a single question on medication adherence was as good as a 3-item questionnaire in predicting HIV viral suppression, although neither had good discriminatory ability. A cut-point close to 90% adherence maximized sensitivity and specificity, although viral suppression was very similar for nearly all measures above 80%.
The effect of high-definition transcranial direct current stimulation intensity on motor performance in healthy adults: a randomized controlled trial
Authors: Lerner Ohad , Friedman Jason , Frenkel-Toledo Silvi
Published: June 2021

Background

The results of transcranial direct current stimulation (tDCS) studies that seek to improve motor performance for people with neurological disorders, by targeting the primary motor cortex, have been inconsistent. One possible reason, among others, for this inconsistency, is that very little is known about the optimal protocols for enhancing motor performance in healthy individuals. The best way to optimize stimulation protocols for enhancing tDCS effects on motor performance by means of current intensity modulation has not yet been determined. We aimed to determine the effect of current intensity on motor performance using–for the first time–a montage optimized for maximal focal stimulation via anodal high-definition tDCS (HD-tDCS) on the right primary motor cortex in healthy subjects.

Methods

Sixty participants randomly received 20-min HD-tDCS at 1.5, 2 mA, or sham stimulation. Participants’ reaching performance with the left hand on a tablet was tested before, during, and immediately following stimulation, and retested after 24 h.

Results

In the current montage of HD-tDCS, movement time did not differ between groups in each timepoint. However, only after HD-tDCS at 1.5 mA did movement time improve at posttest as compared to pretest. This reduction in movement time from pretest to posttest was significantly greater compared to HD-tDCS 2 mA. Following HD-tDCS at 1.5 mA and sham HD-tDCS, but not 2 mA, movement time improved at retest compared to pretest, and at posttest and retest compared to the movement time during stimulation. In HD-tDCS at 2 mA, the negligible reduction in movement time from the course of stimulation to posttest was significantly lower compared to sham HD-tDCS. Across all groups, reaction time improved in retest compared to pretest and to the reaction time during stimulation, and did not differ between groups in each timepoint.

Conclusions

It appears that 2 mA in this particular experimental setup inhibited the learning effects. These results suggest that excitatory effects induced by anodal stimulation do not hold for every stimulation intensity, information that should be taken into consideration when translating tDCS use from the realm of research into more optimal neurorehabilitation.

Trial registration: Clinical Trials Gov, NCT04577768. Registered 6 October 2019 -Retrospectively registered, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000A9B3&selectaction=Edit&uid=U0005AKF&ts=8&cx=buucf0.
The impact of PSTD on service access among people who use drugs in Vancouver, Canada
Authors: Goytan Annemarie , Lee William , Dong Huiru , Hayashi Kanna , Milloy M. J. , Kerr Thomas
Published: June 2021

Background

Settings throughout the United States and Canada are contending with high rates of drug-related overdose. This in turn has prompted efforts to more effectively engage people who use drugs (PWUD) in treatment and care. However, while co-morbid mental disorders are prevalent among PWUD and can undermine access to services, the impact of post-traumatic stress disorder (PTSD) on service access is not known. Therefore, we sought to assess whether PTSD is associated with difficulties accessing health and social services among PWUD in Vancouver, Canada.

Methods

Survey data was derived from two prospective cohorts of PWUD in Vancouver, Canada for the period of April 2017 to November 2018. PTSD was assessed using the PTSD Checklist for the DSM-V (PCL-5). Generalized estimating equations (GEE) was used to estimate the relationship between PTSD and self-reported inability to access health and social services, after adjustment for confounders.

Results

Among 810 participants included in our analysis, 316 (39.0%) participants qualified for a provisional PSTD diagnosis, and 117 (14.4%) reported difficulties accessing services. In a multivariable GEE analysis, a PTSD diagnosis (adjusted odds ratio = 1.69, 95% confidence interval: 1.12–2.55) was independently associated with difficulties accessing services.

Conclusions

We found high rates of PTSD and self-reported difficulties accessing services among PWUD in Vancouver, as well as a positive association between PTSD and difficulties with service access. These findings highlight the need for trauma-informed approaches to service delivery for PWUD, as well as enhanced provider training specific to PTSD.
Perspectives of illicit marijuana growers and traders on commercial legalisation of marijuana in South Africa: considerations for policy formulation
Authors: Manu Emmanuel , Douglas Mbuyiselo , Ntsaba Mohlomi Jafta , Tarkang Elvis Enowbeyang
Published: June 2021

Background

Over the years, there has been a clarion call for legalising marijuana cultivation and trading for commercial purposes in South Africa. Proponents of the call argue that the criminalisation of commercial marijuana cultivation and trading has failed to halt illicit marijuana cultivation and trading. However, the views of those who economically benefit from the illicit marijuana trade on its legalisation remain empirically unsolicited.

Objective

This study aimed to solicit the views of illegal marijuana growers and traders from two selected communities in the Eastern Cape Province of South Africa regarding the commercial legalisation of marijuana cultivation and trading to inform policy on the debate.

Methods

In-depth key informant interview approach was used to interview 18 purposively sampled participants that were selected through the snowball sampling technique. The data were analysed using the thematic content analysis approach.

Results

Participants had both positive and negative perceptions of the possible legalisation of marijuana cultivation and trading. On the positive side, participants indicated freedom from police, the opportunity to grow marijuana on a larger scale, capital acquisition for commercial marijuana cultivation and trading, and regulation of marijuana prices through unionisation as some of the benefits they would derive from the commercial legalisation of marijuana cultivation and trading. On the negative side, loss of their source of livelihood, fall in the price of marijuana and perceived increase in school drop-out rates were the concerns raised.

Conclusion

While participants relished improvement in their economic fortunes upon commercial legalisation of marijuana cultivation and trading, they were also apprehensive about this policy due to the perceived consequences it may have on their livelihoods and communities. We, therefore, recommend that future discussions of the commercial legalisation of marijuana cultivation and trading in South Africa should be done in consultation with illicit marijuana growers and traders to ensure that their interests are safeguarded by such a policy.
Clinical utility of Gafchromic film in an MRI-guided linear accelerator
Authors: Xhaferllari Ilma , Kim Joshua P. , Liyanage Ruchira , Liu Chang , Du Dongsu , Doemer Anthony , Chetty Indrin J. , Wen Ning
Published: June 2021

Background

The purpose of this study is to comprehensively evaluate the suitability of Gafchromic EBT3 and EBT-XD film for dosimetric quality assurance in 0.35 T MR-guided radiotherapy.

Methods

A 0.35 T magnetic field strength was utilized to evaluate magnetic field effects on EBT3 and EBT-XD Gafchromic films by studying the effect of film exposure time within the magnetic field using two timing sequences and film not exposed to MR, the effect of magnetic field exposure on the crystalline structure of the film, and the effect of orientation of the film with respect to the bore within the magnetic field. The orientation of the monomer crystal was qualitatively evaluated using scanning electron microscopy (SEM) compared to unirradiated film. Additionally, dosimetric impact was evaluated through measurements of a series of open field irradiations (0.83 × 0.83-cm2 to 19.92 × 19.92-cm2) and patient specific quality assurance measurements. Open fields were compared to planned dose and an independent dosimeter. Film dosimetry was applied to twenty conventional and twenty stereotactic body radiotherapy (SBRT) patient specific quality assurance cases.

Results

No visual changes in crystal orientation were observed in any evaluated SEM images nor were any optical density differences observed between films irradiated inside or outside the magnetic field for both EBT3 and EBT-XD film. At small field sizes, the average difference along dose profiles measured in film compared to the same points measured using an independent dosimeter and to predicted treatment planning system values was 1.23% and 1.56%, respectively. For large field sizes, the average differences were 1.91% and 1.21%, respectively. In open field tests, the average gamma pass rates were 99.8% and 97.2%, for 3%/3 mm and 3%/1 mm, respectively. The median (interquartile range) 3%/3 mm gamma pass rates in conventional QA cases were 98.4% (96.3 to 99.2%), and 3%/1 mm in SBRT QA cases were 95.8% (95.0 to 97.3%).

Conclusions

MR exposure at 0.35 T had negligible effects on EBT3 and EBT-XD Gafchromic film. Dosimetric film results were comparable to planned dose, ion chamber and diode measurements.
Freestyle aortic root prosthesis in combination with aortic replacement and open anastomosis: a retrospective analysis
Authors: Zientara Alicja , Rosselet-Droux Kim , Bruijnen Hans , Odavic Dragan , Genoni Michele , Dzemali Omer
Published: June 2021

Background

The Freestyle® bioprosthesis is used for pathologies of the aortic root. Additional resection of the ascending aorta and the proximal arch in dissections or aneurysms might be indicated. The aim was to assess mid-term outcome regarding prosthetic performance, stroke, reoperations, and survival in various pathologies comparing patients with and without additional procedures on the ascending aorta and proximal arch focusing on the standardised technique of unilateral antegrade cerebral perfusion under moderate hypothermia.

Methods

Retrospective data analysis of 278 consecutive patients after Freestyle® root replacement between September 2007 and March 2017. Patients were divided in three categories due to the pathology of the aortic root (re-operation vs endocarditis vs dissection). Two groups based on the aortic anastomosis technique (open arch anastomosis (OA) versus non-open arch anastomosis (non-OA) were compared (119 OA vs 159 non-OA). Cardiovascular risk, previous cardiac events, intra- and postoperative data were evaluated. Inferential statistics were performed with Mann-Whitney U-test. Nominal and categorical variables were tested with Fisher-Freeman-Halton exact test. Kaplan-Meier estimate was used to assess survival.

Results

The follow-up rate was 90% (median follow-up: 39.5 months). There were differences in the indication (endocarditis: OA 5 (4.2%) vs non-OA 36 (24%), p < 0.0001; dissection: OA 13 (10.9%) vs non-OA 2 (1.3%); p = 0.0007). OA patients had less perioperative stroke (1 (1%) vs 15 (10%), p = 0.001) and shorter hospital stay (9 vs 12 days, p = 0.0004). There were no differences in the mortality (in-hospital: OA 8 (7%) vs non-OA 8 (5%); p = 0.6; death at follow-up: OA 5 (5%) vs non-OA 15 (11%); p = 0.1). Overall valve performance showed a well-functioning valve in 97.3% at follow-up.

Conclusion

The valve performance showed excellent results regardless of the initial indication. The incidence of stroke was lower in patients receiving an open arch anastomosis using unilateral antegrade cerebral perfusion without elevated mortality or prolonged hospital stay.
Factor VIII replacement prophylaxis in patients with hemophilia A transitioning to adults: a systematic literature review
Authors: Sun Jing , Zhou Xuan , Hu Nan
Published: June 2021

Background

Despite the advantages of prophylactic treatment for hemophilia, patients tend to discontinue or not adhere to it because of several challenges such as long-term use, high cost, young patients transitioning to adolescents, and switch to self-infusion or self-care. The goal of this systematic literature review is to emphasize adherence to and efficiency of prophylactic treatment in adults.

Methods

A literature review was conducted in PubMed, Embase, and Cochrane databases until April 2021 according to PRISMA guidelines, and the protocol was registered with PROSPERO (CRD42020220085). Studies evaluating the efficacy of prophylaxis in enhancing the quality of life were included.

Results

A total of 31 articles involving 2379 patients with hemophilia were included in this systematic review. Of these, 26 studies were observational, questionnaire-based studies, and 5 were randomized controlled trials. The majority of studies reported lower annualized bleeding rates in patients receiving prophylaxis compared with those receiving on-demand treatment or those who discontinued prophylaxis. Standard-dose prophylaxis was reported to be effective in most of the studies. In developing countries like China, data suggest that low doses were administered because of limited available resources. However, standard dose or individualized prophylaxis should be provided to prevent joint damage in the long term. Compared with adults, greater adherence to treatment was observed in patients aged < 16 years.

Conclusion

This systematic review emphasizes the importance of adherence to prophylaxis among young adults transitioning from childhood. In countries like China, low-dose prophylaxis can help in preventing joint bleeds in the short term, but in the long term, standard-dose therapy has shown high adherence among young adults and better joint health, in turn improving the quality of life.
Reductions in midbrain GABAergic and dopamine neuron markers are linked in schizophrenia
Authors: Purves-Tyson Tertia D. , Brown Amelia M. , Weissleder Christin , Rothmond Debora A. , Shannon Weickert Cynthia
Published: June 2021

Reductions in the GABAergic neurotransmitter system exist across multiple brain regions in schizophrenia and encompass both pre- and postsynaptic components. While reduced midbrain GABAergic inhibitory neurotransmission may contribute to the hyperdopaminergia thought to underpin psychosis in schizophrenia, molecular changes consistent with this have not been reported. We hypothesised that reduced GABA-related molecular markers would be found in the midbrain of people with schizophrenia and that these would correlate with dopaminergic molecular changes. We hypothesised that downregulation of inhibitory neuron markers would be exacerbated in schizophrenia cases with high levels of neuroinflammation. Eight GABAergic-related transcripts were measured with quantitative PCR, and glutamate decarboxylase (GAD) 65/67 and GABAA alpha 3 (α3) (GABRA3) protein were measured with immunoblotting, in post-mortem midbrain (28/28 and 28/26 control/schizophrenia cases for mRNA and protein, respectively), and analysed by both diagnosis and inflammatory subgroups (as previously defined by higher levels of four pro-inflammatory cytokine transcripts). We found reductions (21 – 44%) in mRNA encoding both presynaptic and postsynaptic proteins, vesicular GABA transporter (VGAT), GAD1, and parvalbumin (PV) mRNAs and four alpha subunits (α1, α2, α3, α5) of the GABAA receptor in people with schizophrenia compared to controls (p < 0.05). Gene expression of somatostatin (SST) was unchanged (p = 0.485). We confirmed the reduction in GAD at the protein level (34%, p < 0.05). When stratifying by inflammation, only GABRA3 mRNA exhibited more pronounced changes in high compared to low inflammatory subgroups in schizophrenia. GABRA3 protein was expressed by 98% of tyrosine hydroxylase-positive neurons and was 23% lower in schizophrenia, though this did not reach statistical significance (p > 0.05). Expression of transcripts for GABAA receptor alpha subunits 2 and 3 (GABRA2, GABRA3) were positively correlated with tyrosine hydroxylase (TH) and dopamine transporter (DAT) transcripts in schizophrenia cases (GABRA2; r > 0.630, GABRA3; r > 0.762, all p < 0.001) but not controls (GABRA2; r < − 0.200, GABRA3; r < 0.310, all p > 0.05). Taken together, our results support a profound disruption to inhibitory neurotransmission in the substantia nigra regardless of inflammatory status, which provides a potential mechanism for disinhibition of nigrostriatal dopamine neurotransmission.
Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons
Authors: Steg Leonard C. , Shireby Gemma L. , Imm Jennifer , Davies Jonathan P. , Franklin Alice , Flynn Robert , Namboori Seema C. , Bhinge Akshay , Jeffries Aaron R. , Burrage Joe , Neilson Grant W. A. , Walker Emma M. , Perfect Leo W. , Price Jack , McAlonan Grainne , Srivastava Deepak P. , Bray Nicholas J. , Cope Emma L. , Jones Kimberley M. , Allen Nicholas D. , Pishva Ehsan , Dempster Emma L. , Lunnon Katie , Mill Jonathan , Hannon Eilis
Published: June 2021

Induced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the earliest stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age. It has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, we developed the fetal brain clock (FBC), a bespoke epigenetic clock trained in human prenatal brain samples in order to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons. The FBC was tested in two independent validation cohorts across a total of 194 samples, confirming that the FBC outperforms other established epigenetic clocks in fetal brain cohorts. We applied the FBC to DNA methylation data from iPSCs and embryonic stem cells and their derived neuronal precursor cells and neurons, finding that these cell types are epigenetically characterized as having an early fetal age. Furthermore, while differentiation from iPSCs to neurons significantly increases epigenetic age, iPSC-neurons are still predicted as being fetal. Together our findings reiterate the need to better understand the limitations of existing epigenetic clocks for answering biological research questions and highlight a limitation of iPSC-neurons as a cellular model of age-related diseases.
3,3′,5-Triiodothyroacetic acid (TRIAC) induces embryonic ζ-globin expression via thyroid hormone receptor α
Authors: Chen Huiqiao , Wang Zixuan , Yu Shanhe , Han Xiao , Deng Yun , Wang Fuhui , Chen Yi , Liu Xiaohui , Zhou Jun , Zhu Jun , Yuan Hao
Published: June 2021

The human ζ-globin gene (HBZ) is transcribed in primitive erythroid cells only during the embryonic stages of development. Reactivation of this embryonic globin synthesis would likely alleviate symptoms both in α-thalassemia and sickle-cell disease. However, the molecular mechanisms controlling ζ-globin expression have remained largely undefined. Moreover, the pharmacologic agent capable of inducing ζ-globin production is currently unavailable. Here, we show that TRIAC, a bioactive thyroid hormone metabolite, significantly induced ζ-globin gene expression during zebrafish embryogenesis. The induction of ζ-globin expression by TRIAC was also observed in human K562 erythroleukemia cell line and primary erythroid cells. Thyroid hormone receptor α (THRA) deficiency abolished the ζ-globin-inducing effect of TRIAC. Furthermore, THRA could directly bind to the distal enhancer regulatory element to regulate ζ-globin expression. Our study provides the first evidence that TRIAC acts as a potent inducer of ζ-globin expression, which might serve as a new potential therapeutic option for patients with severe α-thalassemia or sickle-cell disease.
Blockade of checkpoint receptor PVRIG unleashes anti-tumor immunity of NK cells in murine and human solid tumors
Authors: Li Yangyang , Zhang Yu , Cao Guoshuai , Zheng Xiaodong , Sun Cheng , Wei Haiming , Tian Zhigang , Xiao Weihua , Sun Rui , Sun Haoyu
Published: June 2021

Background

Although checkpoint-based immunotherapy has shown exciting results in the treatment of tumors, around 70% of patients have experienced unresponsiveness. PVRIG is a recently identified immune checkpoint receptor and blockade of which could reverse T cell exhaustion to treat murine tumor; however, its therapeutic potential via NK cells in mice and human remains seldom reported.

Methods

In this study, we used patient paraffin-embedded colon adenocarcinoma sections, various murine tumor models (MC38 colon cancer, MCA205 fibrosarcoma and LLC lung cancer), and human NK cell- or PBMC-reconstituted xenograft models (SW620 colon cancer) to investigate the effect of PVRIG on tumor progression.

Results

We found that PVRIG was highly expressed on tumor-infiltrating NK cells with exhausted phenotype. Furthermore, either PVRIG deficiency, early blockade or late blockade of PVRIG slowed tumor growth and prolonged survival of tumor-bearing mice by inhibiting exhaustion of NK cells as well as CD8+ T cells. Combined blockade of PVRIG and PD-L1 showed better effect in controlling tumor growth than using either one alone. Depletion of NK or/and CD8+ T cells in vivo showed that both cell types contributed to the anti-tumor efficacy of PVRIG blockade. By using Rag1−/− mice, we demonstrated that PVRIG blockade could provide therapeutic effect in the absence of adaptive immunity. Further, blockade of human PVRIG with monoclonal antibody enhanced human NK cell function and inhibited human tumor growth in NK cell- or PBMC-reconstituted xenograft mice.

Conclusions

Our results reveal the importance of NK cells and provide novel knowledge for clinical application of PVRIG-targeted drugs in future.
Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib
Authors: Fujii Yasutoshi , Ono Atsushi , Hayes C. Nelson , Aikata Hiroshi , Yamauchi Masami , Uchikawa Shinsuke , Kodama Kenichiro , Teraoka Yuji , Fujino Hatsue , Nakahara Takashi , Murakami Eisuke , Miki Daiki , Okamoto Wataru , Kawaoka Tomokazu , Tsuge Masataka , Imamura Michio , Chayama Kazuaki
Published: June 2021

Background

There has been a recent surge in interest in predicting biological effects associated with genomic alterations in order to implement personalized cancer treatment strategies. However, no reports have yet evaluated the utility of profiling blood-based circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN).

Method

We retrospectively performed ctDNA next-generation sequencing (NGS) analysis in 24 patients with advanced HCC at baseline and 4 weeks after initiation of LEN. Association of the changes in variant allele frequencies (VAFs) during treatment and clinical outcome were evaluated.

Results

In total, 131 single nucleotide variants, 17 indels, and 23 copy number variations were detected as somatic alterations in 28, 6, and 12 genes, respectively in 23 of 24 patients. The most frequently altered genes wereTP53(54%),CTNNB1(42%),TERT(42%),ATM(25%), andARID1A(13%). The reduction in the mean frequency of variants (VAFmean) following 4 weeks of LEN treatment was associated with longer progression-free survival. The specificity and sensitivity of the reduction of VAFmeanfor predicting partial response were 0.67 and 1.0, respectively, which were higher than those of serum α-fetoprotein level (0.10 and 0.93, respectively). No association between the mutation status at baseline and the effectiveness of LEN was observed.

Conclusion

Our study demonstrated that somatic alterations could be detected in the majority of advanced HCC patients by ctDNA profiling and that ctDNA-kinetics during LEN treatment was a useful marker of disease progression. These results suggest that ctDNA profiling is a promising method that provides valuable information in clinical practice.