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MicroRNAs (miRNA,miRs) are small noncoding RNAs that are ubiquitously expressed in all mammalian cells. Their primary function is the regulation of nascent RNA transcripts by direct binding to regions on the target. There is now exciting data to suggest that these miRNAs can bind to other miRNAs, and this may have a broader impact on gene regulation in disease states. The oncomiR miR-21 is one of the highest-expressing miRNAs in cancer cells, and in this study, we characterise which miRNAs could be potential targets of miR-21. In cancer cells delivered with a miR-21 mimic, there was an observable shift of the miRNA milieu. We demonstrate that the miR-17-92a cluster, which harbours six miRNA members, may be a target for miR-21 regulation. Additionally, the primary transcript of miR-17-92a was reduced in the presence of miR-21. In the broader context of miR:miR regulation, overexpression of miR-21 shifted the expression of more than 150 miRNAs, including those known to regulate genes in cancer pathways such as the MAPK signalling and FoxO pathways. This study expands upon our limited understanding of miR:miR regulatory network and reinforces the concept that miRNAs can regulate each other, thereby influencing broader gene networks., Competing Interests: Declaration of Competing Interest All authors state that there is no conflict of interest to declare, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The global rise of oropharyngeal cancers (OPC) associated with the human papillomavirus (HPV) type 16 necessitates a deeper understanding of their underlying molecular mechanisms. Our study utilised RNA-sequencing data from The Cancer Genome Atlas (TCGA) to identify and analyse differentially expressed (DE) long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) in HPV16-positive OPC, and to elucidate the interplay within the lncRNA/miRNA/mRNA regulatory network. We revealed 1929 DE lncRNAs and identified a significant expression shift in 37 of these, suggesting a regulatory 'sponge' function for miRNAs that modulate cellular processes. Notably, the lncRNA Linc00911 exhibited decreased expression in HPV16-positive OPC, a change directly attributable to HPV oncogenes E6 and E7 as confirmed by RT-qPCR in cell lines and patient samples. Our comprehensive analysis presents an expansive landscape of ncRNA-mRNA interactions, offering a resource for the ongoing pursuit of elucidating the molecular underpinnings of HPV-driven OPC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: This study provides an analysis of head and neck cancer (HNC) cases over a 20-year period in Ho Chi Minh City, Vietnam. It aims to shed light on HNC's characteristics and trends in this highly populated urban region., Methods: The analysis encompasses 8974 HNC cases, emphasising incidence rates, gender distribution, and the prevalence of different subtypes, including oral cavity, nasopharyngeal, oropharyngeal, and laryngeal/pharyngeal cancers. Ho Chi Minh City was chosen due to its extensive cancer reporting systems and its role as a major urban healthcare centre attracting a wide range of patients., Results: The study reveals an increasing incidence of HNC in Ho Chi Minh City, with a notable predominance of male patients (73 %). The breakdown of HNC cases shows oral cavity cancer at 34 %, nasopharyngeal at 33 %, oropharyngeal at 12 %, and laryngeal/pharyngeal at 21 %. Compared to global averages, Vietnamese patients are diagnosed at an earlier age, with a noticeable trend of decreasing mean age of diagnosis over the study period., Conclusion: This comprehensive study provides valuable insights into the HNC landscape in Ho Chi Minh City, revealing a slightly lower overall incidence but an earlier age of diagnosis compared to global trends. These findings suggest the need for region-specific public health initiatives and further research to clarify the epidemiological features of HNC in Vietnam., Competing Interests: Declaration of Competing Interest No interest to declare, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Head and neck cancers, particularly oropharyngeal cancers (OPC), have been increasingly associated with human papillomavirus (HPV) infections, specifically HPV16. The current methods for HPV16 detection primarily rely on p16 staining or PCR techniques. However, it is important to note the limitations of conventional PCR, as the presence of viral DNA does not always indicate an ongoing viral infection. Moreover, these tests heavily rely on the availability of tissue samples, which can present challenges in certain situations. In this study, we developed a RT-qPCR biplex approach to detect HPV16 oncogenes E6 and E7 RNA in saliva samples from OPC patients. Salivary supernatant was used as the liquid biopsy source. We successfully obtained RNA from salivary supernatant, preserving its integrity as indicated by the detection of several housekeeping genes. Our biplex approach accurately detected E6 and E7 RNA in HPV16-positive cell lines, tissues, and finally in OPC salivary samples. Importantly, the assay specifically targeted HPV16 and not HPV18. This biplexing technique allowed for reduced sample input without compromising specificity. In summary, our approach demonstrates the potential to detect viable HPV16 in saliva from OPC patients. Since the assay measures HPV16 RNA, it provides insights into the transcriptional activity of the virus. This could guide clinical decision-making and treatment planning for individuals with HPV-related OPC., (© 2024. The Author(s).)

Seasonal plasticity in insects is often triggered by temperature and photoperiod changes. When climatic conditions become sub-optimal, insects might undergo reproductive diapause, a form of seasonal plasticity delaying the development of reproductive organs and activities. During the reproductive diapause, the cuticular hydrocarbon (CHC) profile, which covers the insect body surface, might also change to protect insects from desiccation and cold temperature. However, CHCs are often important cues and signals for mate recognition and changes in CHC composition might affect mate recognition. In the present study, we investigated the CHC profile composition and the mating success of Drosophila suzukii in 1- and 5-day-old males and females of summer and winter morphs. CHC compositions differed with age and morphs. However, no significant differences were found between the sexes of the same age and morph. The results of the behavioral assays show that summer morph pairs start to mate earlier in their life, have a shorter mating duration, and have more offspring compared to winter morph pairs. We hypothesize that CHC profiles of winter morphs are adapted to survive winter conditions, potentially at the cost of reduced mate recognition cues., (© 2023. The Author(s).)

BACKGROUNDMajor depressive disorder (MDD) can benefit from novel interventions and personalization. Deep transcranial magnetic stimulation (Deep TMS) targeting the lateral prefrontal cortex (LPFC) using the H1 coil was FDA cleared for treatment of MDD. However, recent preliminary data indicate that targeting the medial prefrontal cortex (MPFC) using the H7 coil might induce outcomes that are as good or even better. Here, we explored whether Deep TMS targeting the MPFC is noninferior to targeting the LPFC and whether electrophysiological or clinical markers for patient selection can be identified.METHODSThe present prospective, multicenter, randomized study enrolled 169 patients with MDD for whom antidepressants failed in the current episode. Patients were randomized to receive 24 Deep TMS sessions over 6 weeks, using either the H1 coil or the H7 coil. The primary efficacy endpoint was the change from baseline to week 6 in Hamilton Depression Rating Scale scores.RESULTSClinical efficacy and safety profiles were similar and not significantly different between groups, with response rates of 60.9% for the H1 coil and 64.2% for the H7 coil. Moreover, brain activity measured by EEG during the first treatment session correlated with clinical outcomes in a coil-specific manner, and a cluster of baseline clinical symptoms was found to potentially distinguish between patients who can benefit from each Deep TMS target.CONCLUSIONThis study provides a treatment option for MDD, using the H7 coil, and initial guidance to differentiate between patients likely to respond to LPFC versus MPFC stimulation targets, which require further validation studies.TRIAL REGISTRATIONClinicalTrials.gov NCT03012724.FUNDINGBrainsWay Ltd.

Background: While premature ejaculation (PE) is a common and disturbing sexual dysfunction in men, current available treatment modalities have limited efficacy and low treatment adherence., Aim: To assess the feasibility, safety, and efficacy of the vPatch, a miniaturized on-demand perineal transcutaneous electrical stimulation device for treating PE., Methods: This prospective bicenter international first-in-human clinical study consisted of 2 arms, was sham controlled, and had a randomized double-blind design. In terms of statistical power calculation, 59 patients aged 21 to 56 years (mean ± SD, 39.8 ± 9.28) with lifelong PE were included. During the initial visit, intravaginal ejaculatory latency time (IELT) was measured over a 2-week run-in period. Eligibility was confirmed in visit 2, based on IELT values, medical and sexual history, and patients' individualized sensory and motor activation thresholds during perineal stimulation with the vPatch. Patients were randomized to the active (vPatch) and sham device groups in a 2:1 ratio, respectively. The vPatch device's safety profile was determined by comparing the incidence of treatment-emergent adverse events. During visit 3, IELTs, Clinical Global Impression of Change scores, and Premature Ejaculation Profile questionnaire outcomes were recorded. Primary end points assessed vPatch device efficacy as mean change in geometric mean IELT; each person was compared with himself, with and without the device, and the sham group was compared with the active group., Outcomes: Outcomes included changes in IELT and Premature Ejaculation Profile before and after treatment, last visit Clinical Global Impression of Change scores, and vPatch safety profile., Results: Of 59 patients, 51 completed the study: 34 in the active group and 17 in the sham group. The baseline geometric mean IELT significantly increased from 67 to 123 seconds (P < .01) in the active group, as compared with an insignificant increase from 63 to 81 seconds (P = .17) in the sham group. The increase in mean IELT in the active group was significantly higher than in the sham group (56 vs 18 seconds, P = .01). IELT significantly increased by 3.1 times in the active vs sham group. The mean ratio of fold change (active:sham) was 1.4, significantly different from 1.0 (P = .02). No serious adverse events were reported., Clinical Implications: Therapeutic use of the vPatch during coitus may become an on-demand, noninvasive, and drug-free treatment for PE., Strengths and Limitations: To our knowledge, this is the first rigorous study investigating whether transcutaneous electrical stimulation during coitus could improve the symptoms of men with lifelong PE. The study is limited by the small number of patients, the exclusion of patients with acquired PE, the short-term follow up, and the use of a device based on a theoretic mechanism of action., Conclusion: We demonstrated the possibility to treat lifelong PE by prolonging coitus on demand, using electric stimulation of ejaculation muscles with the vPatch.Clinical trial registration: NCT03942367 (ClinicalTrials.gov)., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The COVID-19 pandemic resulted in unprecedented government interventions in many people's lives. Opposition to these measures was not only based on policy disagreements but for some founded in an outright denial of basic facts surrounding the pandemic, challenging social cohesion. Conspiracy beliefs have been prolific within various protest groups and require attention, as such attitudes have been shown to be associated with lower rule compliance. Several studies have shown that the characteristics linked to holding COVID-19 conspiracy beliefs are complex and manifold; however, those insights usually rest on cross-sectional studies only. We have less knowledge on whether these cross-sectional correlates also reveal which parts of the population have been newly convinced by conspiracy theories or have dropped their support for them as the pandemic evolved. Using a unique panel data set from Germany, this paper explores a wide range of characteristics and compares the insights gained from cross-sectional associations on the one hand and links to the ways in which people change their views on the other hand. The findings show that cross-sectional analyses miss out on nuanced differences between different groups of temporary and more consistent conspiracy supporters. Specifically, this paper identifies major differences in the profiles of people who have been denying COVID-19 consistently compared to those who changed their minds on the question and those who assessed the reality correctly throughout. In doing so, socio-political and perception-based dimensions are differentiated and distinctions between respondents from East and West Germany explored., Competing Interests: Author TS was employed by d|part. Author JE is a non-salaried director of d|part. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Eichhorn, Spöri, Delhey, Deutsch and Dragolov.)

Clinically, HPV-positive oropharyngeal cancers (OPCs) have been shown to have a distinct prognosis, compared to HPV-negative tumours, particularly in survival rates and responses to treatment. These patients have better survival chances and improved prognosis, indicating that a more exhaustive knowledge of these distinctions would aid in the discovery of clinical approaches for both HPV-positive and negative tumours. Furthermore, there is increasing evidence that HPV-related oropharyngeal cancers constitute an epidemiological, molecular, and clinical distinct form as compared to non-HPV related ones therefore, the treatment of these specific subtype of oropharyngeal cancers should adopt a distinct clinical treatment pipeline. Our review will examine the current approaches for the diagnosis and treatment of OPC and discuss the relevance of de-escalation clinical trials in progress., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Posttraumatic stress disorder (PTSD) is both prevalent and debilitating. While deep transcranial magnetic stimulation (dTMS) has shown preliminary efficacy, exposure therapy remains the most efficacious, though limited, treatment in PTSD. The medial prefrontal cortex (mPFC) is implicated in extinction learning, suggesting that concurrent mPFC stimulation may enhance exposure therapy. In this randomized controlled multicenter trial, the efficacy and safety of mPFC dTMS combined with a brief exposure procedure were studied in patients with PTSD., Methods: Immediately following exposure to their trauma narrative, 125 outpatients were randomly assigned to receive dTMS or sham. Twelve sessions were administered over 4 weeks, with a primary end point of change in 5-week Clinician-Administered PTSD Scale for DSM-5 score. This clinical study did not include biological markers., Results: Clinician-Administered PTSD Scale for DSM-5 score improved significantly in both groups at 5 weeks, though the improvement was smaller in the dTMS group (16.32) compared with the sham group (20.52; p = .027). At 9 weeks, improvement continued in Clinician-Administered PTSD Scale for DSM-5 score in both groups but remained smaller in dTMS (19.0) versus sham (24.4; p = .024)., Conclusions: Both groups showed significant PTSD symptom improvement, possibly from the brief script-driven imagery exposure. While our design was unable to rule out placebo effects, the magnitude and durability of improvement suggest that repeated ultrabrief exposure therapy alone may be an effective treatment for PTSD, warranting additional study. The surprising and unexpected effect in the dTMS group also suggests that repeated mPFC stimulation with the H7 coil may interfere with trauma memory-mediated extinction. Our results provide new insight for dTMS approaches for possible future avenues to treat PTSD., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method increasingly used to treat psychiatric disorders, primarily depression. Initial studies suggest that rTMS may help to treat addictions, but evaluation in multicenter randomized controlled trials (RCTs) is needed. We conducted a multicenter double-blind RCT in 262 chronic smokers meeting DSM-5 criteria for tobacco use disorder, who had made at least one prior failed attempt to quit, with 68% having made at least three failed attempts. They received three weeks of daily bilat-eral active or sham rTMS to the lateral prefrontal and insular cortices, followed by once weekly rTMS for three weeks. Each rTMS session was administered following a cue-induced craving procedure, and participants were monitored for a total of six weeks. Those in abstinence were monitored for additional 12 weeks. The primary outcome measure was the four-week continuous quit rate (CQR) until Week 18 in the intent-to-treat efficacy set, as determined by daily smoking diaries and verified by urine cotinine measures. The trial was registered at ClinicalTrials.gov (NCT02126124). In the intent-to-treat analysis set (N=234), the CQR until Week 18 was 19.4% following active and 8.7% following sham rTMS (X 2 =5.655, p=0.017). Among completers (N=169), the CQR until Week 18 was 28.0% and 11.7%, respectively (X 2 =7.219, p=0.007). The reduction in cigarette consumption and craving was significantly greater in the active than the sham group as early as two weeks into treatment. This study establishes a safe treatment protocol that promotes smoking cessation by stimulating relevant brain circuits. It represents the first large multicenter RCT of brain stimulation in addiction medicine, and has led to the first clearance by the US Food and Drug Administration for rTMS as an aid in smok-ing cessation for adults., (© 2021 World Psychiatric Association.)

Background: Low-dose (≤8 mg) hyperbaric bupivacaine for spinal anesthesia during cesarean delivery results in reduced efficacy, yet as a secondary outcome was associated with reduced frequency of spinal-induced hypotension. Our primary aim was to investigate the relationship between hyperbaric bupivacaine dose and the occurrence of spinal-induced hypotension for cesarean delivery., Methods: Retrospective study of cesarean delivery under spinal or combined spinal anesthesia with hyperbaric bupivacaine in 1 academic institution (2 centers-tertiary and district) from 2012 to 2018. Data were retrieved from the anesthesia information management systems (Metavision, iMDsoft, Tel Aviv, Israel) and the hospital information system, including potential confounding factors, maternal age and weight, hypertensive disease of pregnancy, single/multiple gestation, gestational age, vasopressor administration, planned/urgent surgery, position during anesthesia placement (sitting/lateral), and anesthesiologist seniority. Spinal-induced hypotension was defined as systolic blood pressure that either dropped >20% from baseline or <100 mm Hg. The primary outcome of interest was the incidence of spinal-induced hypotension according to hyperbaric bupivacaine dose. Logistic regression was used to characterize the association between the dose of hyberbaric bupivacaine and spinal-induced hypotension after adjusting for confounding factors., Results: A total of 8226 women were identified. The hyperbaric bupivacaine dose administered was <9 mg for 2395 (29.1%), 9-9.5 mg for 1031 (12.5%), 10 mg for 4155 (50.5%), and >10 mg for 645 (7.8%). We used a cutoff (<10 vs ≥10 mg) to assess for the primary outcome, using multivariable logistic regression. The incidence of at least 1 spinal-induced hypotension episode was higher in patients who received ≥10 mg hyperbaric bupivacaine, 75.8% vs 62.9% for doses below 10 mg, P < .0001; however, even women with lower doses had hypotension. Hyperbaric bupivacaine dose <10 mg was associated with a lower incidence of spinal hypotension, adjusted odds ratio (OR) of 0.774, 95% confidence interval (CI), 0.669-0.897, and P = .0006, adjusted for confounding factors.Umbilical cord pH was available for 2684 (32.6%) cases. There were significantly more neonates with pH < 7.2, among women who received hyperbaric bupivacaine ≥10 mg (10.1%) versus women who received <10 mg (6.8%), P = .0032; however, in the adjusted model, hyperbaric bupivacaine dose ≥10 mg was not associated with pH < 7.2 and an OR of 0.955 (95% CI, 0.631-1.446, P = .829)., Conclusions: Our major finding was that hypotension occurred at all doses of hyperbaric bupivacaine, yet occurrence of spinal hypotension was significantly associated with doses ≥10 mg after adjustment for potential confounders., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 International Anesthesia Research Society.)

Acute kidney injury (AKI) is defined by changes in serum creatinine and urine output (UO). Significant limitations exist regarding accurate ascertainment of urine output even within the intensive care unit. We sought to evaluate an automated urine output collections system and compare it to nursing measurements. We prospectively collected urine output using an electronic urine monitoring system and compared it to charted hourly UO in 44 patients after cardiac surgery at a single university hospital ICU. We calculated UO and oliguria rates and compared them to data from the sensor and from nursing charting. A total of 187 hourly UO measurements were obtained and on average, UO was reported 47 min late, with a median of 18 min, and a maximum of almost 6 h. Patients had a mean hourly UO of 76.3 ml over the observation period. Compared to manual measurements by study personnel, nurses significantly overestimated hourly UO by 19.9 ml (95% CI: 10.3; 29.5; p =  < 0.001). By contrast, the mean difference between the UO measured with the sensor and by study personnel was 2.29 ml (95% CI: - 6.7; 11.3), p = 0.61. Electronic UO monitoring is significantly more accurate than nurse-performed manual measurements in actual intensive care patients. Furthermore, timely ascertainment of UO is difficult to achieve with manual technique, resulting in important delays in detecting oliguria perhaps leading to missed cases of AKI., (© 2021. The Author(s).)

Background: Extracellular vesicles (EVs) have been broadly studied in malaria for nearly a decade. These vesicles carry various functional biomolecules including RNA families such as microRNAs (miRNA). These EVs-derived microRNAs have numerous roles in host-parasite interactions and are considered promising biomarkers for disease severity. However, this field lacks clinical studies of malaria-infected samples. In this study, EV specific miRNAs were isolated from the plasma of patients from Thailand infected with Plasmodium vivax and Plasmodium falciparum. In addition, it is postulated that these miRNAs were differentially expressed in these groups of patients and had a role in disease onset through the regulation of specific target genes., Methods: EVs were purified from the plasma of Thai P. vivax-infected patients (n = 19), P. falciparum-infected patients (n = 18) and uninfected individuals (n = 20). EV-derived miRNAs were then prepared and abundance of hsa-miR-15b-5p, hsa-miR-16-5p, hsa-let-7a-5p and hsa-miR-150-5p was assessed in these samples. Quantitative polymerase chain reaction was performed, and relative expression of each miRNA was calculated using hsa-miR-451a as endogenous control. Then, the targets of up-regulated miRNAs and relevant pathways were predicted by using bioinformatics. Receiver Operating Characteristic with Area under the Curve (AUC) was then calculated to assess their diagnostic potential., Results: The relative expression of hsa-miR-150-5p and hsa-miR-15b-5p was higher in P. vivax-infected patients compared to uninfected individuals, but hsa-let-7a-5p was up-regulated in both P. vivax-infected patients and P. falciparum-infected patients. Bioinformatic analysis revealed that these miRNAs might regulate genes involved in the malaria pathway including the adherens junction and the transforming growth factor-β pathways. All up-regulated miRNAs could potentially be used as disease biomarkers as determined by AUC; however, the sensitivity and specificity require further investigation., Conclusion: An upregulation of hsa-miR-150-5p and hsa-miR-15b-5p was observed in P. vivax-infected patients while hsa-let-7a-5p was up-regulated in both P. vivax-infected and P. falciparum-infected patients. These findings will require further validation in larger cohort groups of malaria patients to fully understand the contribution of these EVs miRNAs to malaria detection and biology.

Cannabidiol (CBD) is the main nonpsychoactive component of the cannabis plant. It has been associated with antiseizure, antioxidant, neuroprotective, anxiolytic, anti-inflammatory, antidepressant, and antipsychotic effects. PTL101 is an oral gelatin matrix pellets technology-based formulation containing highly purified CBD embedded in seamless gelatin matrix beadlets. Study objectives were to evaluate the safety and tolerability of PTL101 containing 10 and 100 mg CBD, following single administrations to healthy volunteers and to compare the pharmacokinetic profiles and relative bioavailability of CBD with Sativex oromucosal spray (the reference product) in a randomized, crossover study design. Administration of PTL101 containing 10 CBD, led to a 1.7-fold higher C max and 1.3-fold higher AUC compared with the oromucosal spray. T max following both modes of delivery was 3-3.5 hours postdosing. CBD exhibited about a 1-hour lag in absorption when delivered via PTL101. A 10-fold increase in the dose resulted in an ∼15-fold increase in C max and AUC. Bioavailability of CBD in the 10-mg PTL101 dose was 134% relative to the reference spray. PTL101 is a pharmaceutical-grade, user-friendly oral formulation that demonstrated safe and efficient delivery of CBD and therefore could be an attractive candidate for therapeutic indications., (© 2017, The American College of Clinical Pharmacology.)

Human papillomavirus (HPV), notably type 16, is a risk factor for up to 75% of oropharyngeal squamous cell carcinomas (SCC). It has been demonstrated that small non-coding RNAs known as microRNAs play a vital role in the cellular transformation process. In this study, we used an LNA array to further investigate the impact of HPV16 on the expression of microRNAs in oropharyngeal (tonsillar) cancer. A number of miRNAs were found to be deregulated, with miR-496 showing a four-fold decrease. Over-expression of the high risk E6 oncoprotein down-regulated miR-496, impacting upon the post-transcriptional control of the transcription factor E2F2. These HPV specific miRNAs were integrated with the HPV16 interactome to identify possible mechanistic pathways. These analyses provide insights into novel molecular interactions between HPV16 and miRNAs in oropharyngeal cancers., (Copyright © 2018. Published by Elsevier Inc.)

There is a growing clinical interest in developing and commercializing pharmaceutical-grade cannabinoid products, containing primarily tetrahydrocannabinol (THC) and cannabidiol (CBD). The oral bioavailability of THC and CBD is very low due to extensive "first-pass" metabolism. A novel oral THC and CBD formulation, PTL401, utilizing an advanced self-emulsifying oral drug delivery system, was designed to circumvent the "first-pass" effect. In this study, the bioavailability of THC and CBD from the PTL401 capsule was compared with similar doses from a marketed reference oromucosal spray (Sativex ® ). Fourteen healthy male volunteers received, on separate treatment days, either a single dose of PTL401 or an equivalent dose of the oromucosal spray. Blood samples for pharmacokinetic analyses were collected, and safety and tolerability were assessed. PTL401 yielded 1.6-fold higher plasma C max than the equivalent dose of the oromucosal spray, for both THC and CBD. Their relative bioavailability was also higher (131% and 116% for CBD and THC, respectively). Values of T max were significantly shorter for both CBD and THC (median of 1.3 h for PTL401 vs. 3.5 h for the spray). The pharmacokinetic profiles of the active 11-OH-THC metabolite followed the same pattern as THC for both routes of delivery. No outstanding safety concerns were noted following either administration. We conclude that PTL401 is a safe and effective delivery platform for both CBD and THC. The relatively faster absorption and improved bioavailability, compared to the oromucosal spray, justifies further, larger scale clinical studies with this formulation., (Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Major depressive disorder (MDD) is a prevalent and disabling condition, and many patients do not respond to available treatments. Deep transcranial magnetic stimulation (dTMS) is a new technology allowing non-surgical stimulation of relatively deep brain areas. This is the first double-blind randomized controlled multicenter study evaluating the efficacy and safety of dTMS in MDD. We recruited 212 MDD outpatients, aged 22-68 years, who had either failed one to four antidepressant trials or not tolerated at least two antidepressant treatments during the current episode. They were randomly assigned to monotherapy with active or sham dTMS. Twenty sessions of dTMS (18 Hz over the prefrontal cortex) were applied during 4 weeks acutely, and then biweekly for 12 weeks. Primary and secondary efficacy endpoints were the change in the Hamilton Depression Rating Scale (HDRS-21) score and response/remission rates at week 5, respectively. dTMS induced a 6.39 point improvement in HDRS-21 scores, while a 3.28 point improvement was observed in the sham group (p=0.008), resulting in a 0.76 effect size. Response and remission rates were higher in the dTMS than in the sham group (response: 38.4 vs. 21.4%, p=0.013; remission: 32.6 vs. 14.6%, p=0.005). These differences between active and sham treatment were stable during the 12-week maintenance phase. dTMS was associated with few and minor side effects apart from one seizure in a patient where a protocol violation occurred. These results suggest that dTMS constitutes a novel intervention in MDD, which is efficacious and safe in patients not responding to antidepressant medications, and whose effect remains stable over 3 months of maintenance treatment., (© 2015 World Psychiatric Association.)

Ion chromatographic (IC) methods have been compared in order to achieve an optimal separation of fluoride, acetate and formate under various elution conditions on two formerly introduced analytical columns (i and ii) and a novel one (iii): (i) an IonPac AS14 (250 mm × 4 mm I.D.), (ii) Allsep A-2 (150 mm × 4.6mm I.D.), and (iii) an IC SI-50 4E (250 mm (length) × 4mm (internal diameter - I.D.)). The IC conditions for the separation of the anions concerned were optimized on the IC SI-50 4E column. A near baseline separation of these anions was attained on the IonPac AS14, whereas the peaks of fluoride and acetate could not be resolved on the Allsep A-2. A baseline separation for the three anions was achieved on the IC SI-50 4E column, when applying an eluent mixture of 3.2 mmol/L Na(2)CO(3) and 1.0 mmol/L NaHCO(3) with a flow rate of 1.0 mL/min. The highest precision of 1.7, 3.0 and 2.8% and the best limits of detection (LODs) of 0.014, 0.22 and 0.17 mg/L for fluoride, acetate and formate, respectively, were obtained with the IC SI-50 4E column. Hence, this column was applied for the determination of the acetic and formic acid contents of air samples taken by means of passive gaseous sampling at the Metropolitan Museum of Art in New York, USA. Atmospheric concentrations of acetic and formic acid up to 1050 and 450 μg/m(3), respectively, were found in non-aerated showcases of the museum. In galleries and outdoors, rather low levels of acetic and formic acid were detected with average concentrations of 50 and 10 μg/m(3), respectively. The LOD data of acetate and formate on the IC SI-50 4E column correspond to around 0.5 μg/m(3) for both acetic and formic acid in air samples., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Transcranial magnetic stimulation (TMS) enables non-surgical activation of specific brain areas. TMS over the prefrontal cortex (PFC) is emerging as a significant tool that can augment or replace non/partially effective antidepressant medications. Deep TMS (DTMS) utilizes newly developed coils that enable effective stimulation of deeper cortical layers involved in the pathophysiology of depression., Objectives: We aimed to assess the H1-DTMS coil as an add-on to antidepressants in treating patients with major depression. We also intended to evaluate whether the antidepressant outcome of DTMS treatment is affected by a cognitive-emotional procedure performed during stimulation., Methods: 57 patients were enrolled in the study that included 4 weeks of daily 20 Hz stimulation sessions and additional 4 weekly sessions as a short maintenance phase. Two subgroups of patients received either positive or negative cognitive-emotional reactivation along with the stimulation sessions., Results: 21 of 46 patients (46%) who received at least 10 stimulation sessions achieved response (improvement of ≥ 50% in the Hamilton Depression Rating Scale (HDRS)) and 13 of them (28%) achieved remission (HDRS-24 ≤ 10) by the end of the daily treatment phase. Improvements were smaller in the negatively reactivated group and Beck Depression Inventory scores were not significantly improved in this group., Conclusions: DTMS over the PFC proved to be safe and effective in augmenting antidepressant medications. Negative cognitive-emotional reactivation can disrupt the therapeutic effect of DTMS. A large sham controlled study is required to further establish the effectiveness of DTMS as an augmentation treatment and the role of cognitive reactivation during stimulation., (© 2010 Elsevier B.V. All rights reserved.)

Endovascular surgery has presented a high evolution since 1960 with Charles Dotter, who changed the concept of catheter utilization as a mean to diagnose and introduce therapeutic in interventionist vascular environment. The first reports of bleeding control of gastrointestinal and transluminal angioplasty input the development of new techniques for endovascular access, and new materials use, such as microcatheters and embolic agents, become this procedure effective and viable for treatment of several pathologies. The embolization of several organs of human body is a procedure carried out for more than 30 years all over the world showing safety, efficacy and of simple execution. In obstetrics and gynecology, particularly, the first reports refer to pelvic hemorrhage control of varied etiology, including pelvic trauma, bladder and gynecology neoplasia, anteriovenous fistulas and puerperal hemorrhages. The embolization of uterine myoma appears in the 1990's as an alternative for treat of uterine leiomyoma, and a number of studies try to clarify the risks and benefits of this procedure. It is a multidisciplinary technique, with diagnostic and indication performed by gynecologist and the procedure done by interventional vascular radiologist. This review is a critical analysis of interventionist vascular radiologic methods and its main therapeutic indications in gynecology.

Daily and seasonal variation in the total elemental, organic carbon (OC) and elemental carbon (EC) content and mass of PM(2.5) were studied at industrial, urban, suburban and agricultural/rural areas. Continuous (optical Dustscan, standard tapered element oscillating micro-balance (TEOM), TEOM with filter dynamics measurement system), semi-continuous (Partisol filter-sampling) and non-continuous (Dekati-impactor sampling and gravimetry) methods of PM(2.5) mass monitoring were critically evaluated. The average elemental fraction accounted for 2-6% of the PM(2.5) mass measured by gravimetry. Metals, like K, Mn, Fe, Cu, Zn and Pb were strongly inter-correlated, also frequently with non-metallic elements (P, S, Cl and/or Br) and EC/OC. A high OC/EC ratio (2-9) was generally observed. The total carbon content of PM(2.5) ranged between 3 and 77% (averages: 12-32%), peaking near industrial/heavy trafficked sites. Principal component analysis identified heavy oil burning, ferrous/non-ferrous industry and vehicular emissions as the main sources of metal pollution., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

In this paper, we assess the status of the air quality in the Lake Baikal region which is strongly influenced by the presence of anthropogenic pollution sources. We combined the local data, with global databases, remote sensing imagery and modelling tools. This approach allows to inventorise the air-polluting sources and to quantify the air-quality concentration levels in the Lake Baikal region to a reasonable level, despite the fact that local data are scarcely available. In the simulations, we focus on the month of July 2003, as for this period, validation data are available for a number of ground-based measurement stations within the Lake Baikal region.

For the isocratic ion chromatography (IC) separation of low-molecular-mass organic acids and inorganic anions three different anion-exchange columns were studied: IonPac AS14 (9 microm particle size), Allsep A-2 (7 microm particle size), and IC SI-50 4E (5 microm particle size). A complete baseline separation for all analyzed anions (i.e., F(-), acetate, formate, Cl(-), NO(2)(-), Br(-), NO(3)(-), HPO(4)(2-) and SO(4)(2-)) in one analytical cycle of shorter than 17 min was achieved on the IC SI-50 4E column, using an eluent mixture of 3.2mM Na(2)CO(3) and 1.0mM NaHCO(3) with a flow rate of 1.0 mL min(-1). On the IonPac AS14 column, it was possible to separate acetate from inorganic anions in one run (i.e., less than 9 min), but not formate, under the following conditions: 3.5mM Na(2)CO(3) plus 1.0mM NaHCO(3) with a flow rate of 1.2 mL min(-1). Therefore, it was necessary to adapt a second run with a 2.0mM Na(2)B(4)O(7) solution as an eluent under a flow rate of 0.8 mL min(-1) for the separation of organic ions, which considerably enlarged the analysis time. For the Allsep A-2 column, using an eluent mixture of 1.2mM Na(2)CO(3) plus 1.5mM NaHCO(3) with a flow rate of 1.6 mL min(-1), it was possible to separate almost all anions in one run within 25 min, except the fluoride-acetate critical pair. A Certified Multianion Standard Solution PRIMUS for IC was used for the validation of the analytical methods. The lowest RSDs (less than 1%) and the best LODs (0.02, 0.2, 0.16, 0.11, 0.06, 0.05, 0.04, 0.14 and 0.09 mg L(-1) for F(-), Ac(-), For(-), Cl(-), NO(2)(-), Br(-), NO(3)(-), HPO(4)(2-) and SO(4)(2-), respectively) were achieved using the IC SI-50 4E column. This column was applied for the separation of concerned ions in environmental precipitation samples such as snow, hail and rainwater.

Mass, major ionic components (MICs) of PM2.5, and related gaseous pollutants (SO2, NO(x), NH3, HNO2, and HNO3) were monitored over six locations of different anthropogenic influence (industrial, urban, suburban, and rural) in Belgium. SO4(2-), NO3-, NH4+, and Na+ were the primary ions of PM2.5 with averages diurnal concentrations ranging from 0.4-4.5, 0.3-7.6, 0.9-4.9, and 0.4-1.2 microg m(-3), respectively. MICs formed 39% of PM2.5 on an average, but it could reach up to 80-98%. The SO2, NO, NO2, HNO2, and HNO3 levels showed high seasonal and site-specific fluctuations. The NH3 levels were similar over all the sites (2-6 microg m(-3)), indicating its relation to the evenly distributed animal husbandry activities. The sulfur and nitrogen oxidation ratios for PM2.5 point towards a low-to-moderate formation of secondary sulfate and nitrate aerosols over five cities/towns, but their fairly intensive formation over the rural Wingene. Cluster analysis revealed the association of three groups of compounds in PM2.5: (i) NH4NO3, KNO3; (ii) Na2SO4; and (iii) MgCl2, CaCl2, MgF2, CaF2, corresponding to anthropogenic, sea-salt, and mixed (sea-salt + anthropogenic) aerosols, respectively. The neutralization and cation-to-anion ratios indicate that MICs of PM2.5 appeared mostly as (NH4)2SO4 and NH4NO3 salts. Sea-salt input was maximal during winter reaching up to 12% of PM2.5. The overall average Cl-loss for sea-salt particles of PM2.5 at the six sites varied between 69 and 96% with an average of 87%. Principal component analysis revealed vehicular emission, coal/wood burning and animal farming as the dominating sources for the ionic components of PM2.5.

Forty relapsing multiple sclerosis patients with 1-15 gadolinium (Gd)-enhancing lesions on screening brain magnetic resonance imaging (MRI) and Expanded Disability Status Scale (EDSS) scores 0-6.5 were randomized to receive short-term induction therapy with mitoxantrone (three monthly 12 mg/m(2) infusions) followed by 12 months of daily glatiramer acetate (GA) therapy 20 mg/day subcutaneously for a total of 15 months (M-GA, n = 21) or daily GA 20 mg/day for 15 months (GA, n = 19). MRI scans were performed at months 6, 9, 12 and 15. The primary measure of outcome was the incidence of adverse events; secondary measures included number of Gd-enhanced lesions, confirmed relapses and EDSS changes. Except age, baseline demographic characteristics were well matched in both treatment arms. Both treatments were safe and well tolerated. M-GA induction produced an 89% greater reduction (relative risk (RR) = 0.11, 95% confidence interval (CI): 0.04-0.36, p = 0.0001) in the number of Gd-enhancing lesions at months 6 and 9 and a 70% reduction (RR = 0.30, 95% CI: 0.11-0.86, p = 0.0147) at months 12 and 15 versus GA alone. Mean relapse rates were 0.16 and 0.32 in the M-GA and GA groups, respectively. Short-term immunosuppression with mitoxantrone followed by daily GA for up to 15 months was found to be safe and effective, with an early and sustained decrease in MRI disease activity.

A method for the separation of acetate and formate anions by ion chromatography has been optimized under various measurement conditions (e.g. the composition of the mobile phase, and the flow rate of the eluent). For this purpose, two different analytical columns were examined: the IonPac AS14 (250 mm x 4 mm i.d.; designed mostly for the separation of inorganic anions) and the Allsep A-2 (150 mm x 4.6 mm i.d.; designed for the separation of low-molecular mass organic acids). However, nearly baseline separation of acetate and formate has been found on each column using the following conditions: (i) IonPac AS14 column and 2.0 mM Na2B4O7 solution as an eluent with a flow rate of 1.0 ml/min, or (ii) Allsep A-2 column and an eluent containing a mixture of 1.2 mM Na2CO3 plus 1.5 mM NaHCO3 with a flow rate of 1.3 ml/min. Additionally, the separation of fluoride from acetate and formate on both columns was studied. On the IonPac AS14 column it was possible to separate all three investigated anions. However, on the Allsep A-2 column, when the concentration of fluoride was comparable to, or higher than acetate, it was impossible to achieve good separation of these two anions, even using the optimized elution procedure. Therefore, the measurements of real samples were carried out with the use of IonPac AS14 column. The concentrations of acetate and formate have been determined in the air samples of the Cathedral of Cologne (Germany), after sampling the corresponding acids by passive diffusion tubes. Average concentrations of 122 and 9 microg/m(3) for acetic and formic acids were found, respectively, inside the Cathedral and in a depot with medieval stained glass panels.

Unlabelled: Guidelines for volume replacement for acutely hemorrhaged and hemodiluted trauma patients have not been well established., Purpose: To evaluate the effects of acute hemodilution on mean arterial pressure (MAP), and responsiveness of acutely hemodiluted and subsequently hemorrhaged rats to different volume therapies., Methods: 180 rats were hemodiluted to simulate hemorrhaged trauma patients with persistent bleeding after high volume replacement with isotonic solutions. Thirty hemodiluted [Anemia (ANE) group] animals received no further treatment. The remaining 150 animals were subjected to hypovolemic shock and randomized into five groups, according to the treatment option employed: Control (CTL) animals did not receive subsequent treatment after hemorrhagic hypovolemia, SAL4 animals received isotonic saline 4 mL/kg, SAL32 animals received isotonic saline 32 mL/kg, HS animals received hypertonic saline 4 mL/kg and BLD animals received re-infusion of drawn blood., Results: Highest mean arterial pressure (MAP) was achieved by BLD, followed by SAL32 and HS. MAP after treatment of BLD, HS, SAL32 and ANE were higher than CTL (p=0.036). At 85 and 95 minutes of experiment, SAL4, SAL32 and HS presented the lowest hematocrit levels (p<0.01). At day 3, ANE, CTL and HS had the highest hematocrit. SAL4 and CTL groups presented the highest mortality rates., Conclusion: Hypertonic saline is an effective and safe initial therapy for hemodiluted rats undergoing hemorrhagic shock, with an overall outcome comparable to blood replacement or high volume isotonic saline administration.

Umbilical nodes are rare. The metastatic involvement of the region was first described in 1846. Sister Mary Joseph was the first observer to establish the correlation between carcinomas and umbilical nodes. The umbilical node may be the sole presenting sign of cancer and is usually associated with advanced disease and poor prognosis. A 64-year-old woman, previously healthy, presented vague abdominal discomfort and a hard umbilical nodule for 1 week, which was first diagnosed as an incarcerated umbilical hernia. She underwent a new clinical assessment and biopsy. After immunohistochemical analysis and computerized tomography, she was diagnosed with pancreatic cancer. The clinical staging showed advanced disease with distant metastasis. She received palliative chemotherapy. After 8 months, she was alive in poor clinical condition. Clinical suspicion should lead to a careful additional evaluation whenever an umbilical nodule presents with malignant signs.

Objective: To analyze surgical and pathological parameters and outcome and prognostic factors of patients with nonsmall cell lung cancer (NSCLC) who were admitted to a single institution, as well as to correlate these findings to the current staging system., Method: Seven hundred and thirty seven patients were diagnosed with NSCLC and admitted to Hospital do Cancer A. C. Camargo from 1990 to 2000. All patients were included in a continuous prospective database, and their data was analyzed. Following staging, a multidisciplinary team decision on adequate management was established. Variables included in this analysis were age, gender, histology, Karnofsky index, weight loss, clinical stage, surgical stage, chemotherapy, radiotherapy, and survival rates., Results: 75.5% of patients were males. The distribution of histologic type was squamous cell carcinoma 51.8%, adenocarcinoma 43.1%, and undifferentiated large cell carcinoma 5.1%. Most patients (73%) presented significant weight loss and a Karnofsky index of 80%. Clinical staging was IA 3.8%, IB 9.2%, IIA 1.4%, IIB 8.1%, IIIA 20.9%, IIIB 22.4%, IV 30.9%. Complete tumor resection was performed in 24.6% of all patients. Surgical stage distribution was IA 25.3%, IB 1.4%, IIB 17.1%, IIIA 16.1%, IIIB 20.3%, IV 11.5%. Chemotherapy and radiotherapy were considered therapeutic options in 43% and 72%, respectively. The overall 5-year survival rate of nonsmall cell lung cancer patients in our study was 28%. Median survival was 18.9 months., Conclusions: Patients with NSCLC who were admitted to our institution presented with histopathologic and clinical characteristics that were similar to previously published series in cancer hospitals. The best prognosis was associated with complete tumor resection with lymph node dissection, which is only achievable in earlier clinical stages.

Embryogenesis and plant regeneration have been obtained from isolated immature pollen of two poplar hybrids (Populus nigra L. x hybrid 'Aue1' and 'Aue2'). In total, 1487 calli or embryos, respectively, larger than 1 mm were generated in a 2-year study. By using a cytokinin containing induction medium, on average 19 calli per responsive immature catkin were formed. Additional supplementation with auxin in 2002 increased the frequency to 72 calli per catkin. Microsatellite marker analyses confirmed haploid origin in most regenerants studied. So far six out of eight obtained regenerative callus lines have maintained their haploid level up to 24 months of development. A number of haploid and doubled haploid plants of different lines are available and have been transferred to soil.

We have investigated the somatic activity of the maize Activator (Ac) element in haploid and diploid aspen with the objective of developing an efficient transposon-based system for gene isolation in the model tree species Populus. It was shown that Ac is reinserted, frequently into or near coding regions in aspen, and therefore can be used for gene tagging studies. A number of phenotypic variants were also found following transformation of constructs harbouring the rolC gene. Comparative analyses of T-DNA flanking regions of variants and wild type lines indicate that T-DNA insertion has occurred in or near coding regions. However, the frequency of T-DNA insertion into genes is about one half of the frequency of Ac insertion hitting coding sequences. The results obtained give a proof-of-concept for transposon tagging in a tree system. Given the long generation cycles in tree species, gene tagging strategies are practical only to obtain dominant gain-of-function mutants that do not require selfing or test crossing. In order to obtain recessive loss-of-function mutants, we have regenerated haploid lines from immature pollen. These lines were successfully transformed with a construct containing the rolC transgene from Agrobacterium rhizogenes and Ac element from maize. The results indicate that Ac is also active in haploid aspen and hence can be used in general for gene tagging in trees.

The results of a study of the elemental and ionic composition of the ambient aerosol in and around Antwerp are presented. Four sampling campaigns were performed, covering all seasons. The samples were obtained by filtration and impaction methods. Subsequently, the filters were analyzed by X-ray fluorescence spectrometry for elements, and the impactor substrates were leached with water and analyzed by ion chromatography for ions. When comparing the results of the chemical analysis with the meteorological information, it was found that the concentration of certain elements and ions in aerosol samples was affected considerably by the location of the sampling site and by the meteorological conditions. In relatively less polluted places like small towns and rural regions around Antwerp, the concentrations of some elements and ions showed qualitatively a positive or negative correlation in their time variations with the amount of precipitation. Hence, we suppose that in the first case these elements and ions are contained mainly in the more hygroscopic fraction (the most apparent is the behavior of Na and Cl), and that in the second case, the elements are mainly present in the less hygroscopic fraction of the ambient aerosol. However, this behavior of the elements and ions may be different for various particle size ranges. In the highly urbanized and industrial sites close to the central and industrial parts of Antwerp, these correlations were not found. This could be connected with the high and variable local aerosol generation rate, when only heavy rains are able to provide a sufficient removal of the aerosols from the atmosphere.

Gastric cancer is uncommon before the fifth decade of life. The appearance of adenocarcinoma in young adults has motivated molecular studies that aimed to identify inherited mutations. Moreover, carcinoma of the stomach in the young adult is sufficiently rare to generate considerable interest in each occurrence of it, especially when it occurs in the gastroesophageal junction. We report a case of gastric carcinoma in a 13-year-old girl, who was referred to our service with weakness, malaise, weight loss, and slight dysphagia. An upper endoscopy with biopsy revealed a gastric Borrmann III tumor, with invasion of the distal esophagus; histopathological analysis revealed a moderately differentiated adenocarcinoma. During staging, she was diagnosed with several metastases, including the lymph nodes, liver, spleen, and ovary. She was referred for radiochemotherapy and died within 4 months. We should consider and investigate the possibility of malignancy even in young patients with persistent symptoms or anemia, in order to diagnose this malignancy at earlier stages.

Different ways of conceptualizing and measuring change in attitudes during transition to motherhood are examined. A series of analyses was performed on data from a cross-sectional sample (N = 667) and a smaller longitudinal sample (n = 48) to demonstrate sound psychometric properties for 2 new scales and to show construct comparability across different phases of childbearing. For Childbearing Attitudes Questionnaire, results demonstrated equality of covariance for 16 scales and comparability of structure and meaning of 4 higher order factors--identification with motherhood, social orientation, self-confidence, and negative aspects of giving birth. For Mothering Self-Definition Questionnaire, results demonstrated equality of covariance of 5 scales and comparability of structure and meaning of a single higher order factor, interpreted as reflecting positive feelings about one's mothering characteristics. Analyses of correlations and mean differences identified areas of change and stability.

Adolescents (75 males, 150 females) assumed the role of parent surrogate and responded to nine problem situations involving younger siblings. Responses were coded into 21 categories--grouped as high, medium, low and non-power as well as "effective" or "ineffective"--and analyzed by sex, grade (10, 11, or 12) and birth order (first-, second-, or laterborn). Ninety-two percent of responses were categorized as "ineffective" (i.e., not communicating own or sibling's feelings). Seniors used less high and more medium and non-power responses than younger students. Most students, particularly females, expressed interest in joining a group to learn better ways of relating to younger siblings.