The effect of nocebo explanation and empathy on side-effect expectations of medication use following a fictional GP consultation.

The simple act of informing patients about side-effects increases the likelihood they will experience them (i.e. the nocebo effect). Explaining this psychological phenomenon could help to reduce side-effect experience, however, it is yet to be explored if this can be applied to clinical settings where new medication is prescribed. In addition, the degree to which a health-care provider empathetically communicates this to patients may have an impact. To investigate this, we carried out 2 × 2 factorial trial to assess the effect of nocebo explanation and empathy (plus their interaction) on side-effect expectations following a fictional GP consultation prescribing a new medication. Overall, 208 participants were randomised to watch one of the four fictive GP consultations and play the role of the patient. In all videos, participants received information about the reason for the consultation, the recommendation of a new fictive medicine, how to take it, benefits and side-effects. The videos differed in whether the GP provided an explanation of the nocebo effect (yes/no) and whether they communicated in an empathetic style (yes/no). After watching the video, participants were asked about their side-effect expectations and rated the quality of the GP's communication. Two-way ANOVAs revealed no main effect of nocebo explanation on expectation of side-effects warned or not warned about in the consultation. However, there was a main effect of empathy, with participants watching the empathetic consultations having significantly lower expectations of non-warned-about side-effects. There was no significant interaction. Findings suggest that explaining the nocebo effect and GP empathy did little to allay expectations of side-effects that were specifically mentioned in the consultation. However, GP empathy had an effect by helping to reduce additional side-effect expectations participants still had. Future work should extend these findings to real GP consultations where the full dimensions of empathy can be explored.

Characterizing the Blood-Stage Antimalarial Activity of Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum.

BACKGROUND: The long-acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood-stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD)-deficient individuals. METHODS: Healthy adults with normal levels of G6PD were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8. Parasitemia and concentrations of tafenoquine and the 5,6-orthoquinone metabolite in plasma/whole blood/urine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48 ± 2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population. RESULTS: Twelve participants were inoculated and administered 200 mg (n = 3), 300 mg (n = 4), 400 mg (n = 2), or 600 mg (n = 3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 hours and 4.2 hours, respectively) was faster than with 200 mg or 300 mg (11.8 hours and 9.6 hours, respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants) but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 106 and 109, respectively, in a 60-kg adult. CONCLUSIONS: Although a single dose of tafenoquine exhibits potent P. falciparum blood-stage antimalarial activity, the estimated doses to effectively clear asexual parasitemia will require prior screening to exclude G6PD deficiency. Clinical Trials Registration. Australian and New Zealand Clinical Trials Registry (ACTRN12620000995976).

Transmission Blocking Activity of Low-dose Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum.

BACKGROUND: Blocking the transmission of parasites from humans to mosquitoes is a key component of malaria control. Tafenoquine exhibits activity against all stages of the malaria parasite and may have utility as a transmission blocking agent. We aimed to characterize the transmission blocking activity of low-dose tafenoquine. METHODS: Healthy adults were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Piperaquine was administered on days 9 and 11 to clear asexual parasitemia while allowing gametocyte development. A single 50-mg oral dose of tafenoquine was administered on day 25. Transmission was determined by enriched membrane feeding assays predose and at 1, 4, and 7 days postdose. Artemether-lumefantrine was administered following the final assay. Outcomes were the reduction in mosquito infection and gametocytemia after tafenoquine and safety parameters. RESULTS: Six participants were enrolled, and all were infective to mosquitoes before tafenoquine, with a median 86% (range, 22-98) of mosquitoes positive for oocysts and 57% (range, 4-92) positive for sporozoites. By day 4 after tafenoquine, the oocyst and sporozoite positivity rate had reduced by a median 35% (interquartile range [IQR]: 16-46) and 52% (IQR: 40-62), respectively, and by day 7, 81% (IQR 36-92) and 77% (IQR 52-98), respectively. The decline in gametocyte density after tafenoquine was not significant. No significant participant safety concerns were identified. CONCLUSIONS: Low-dose tafenoquine (50 mg) reduces P. falciparum transmission to mosquitoes, with a delay in effect.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Coadministered Ruxolitinib and Artemether-Lumefantrine in Healthy Adults.

Despite repeated malaria infection, individuals living in areas where malaria is endemic remain vulnerable to reinfection. The Janus kinase (JAK1/2) inhibitor ruxolitinib could potentially disrupt the parasite-induced dysfunctional immune response when administered with antimalarial therapy. This randomized, single-blind, placebo-controlled, single-center phase 1 trial investigated the safety, tolerability, and pharmacokinetic and pharmacodynamic profile of ruxolitinib and the approved antimalarial artemether-lumefantrine in combination. Ruxolitinib pharmacodynamics were assessed by inhibition of phosphorylation of signal transducer and activator of transcription 3 (pSTAT3). Eight healthy male and female participants ages 18 to 55 years were randomized to either ruxolitinib (20 mg) (n = 6) or placebo (n = 2) administered 2 h after artemether-lumefantrine (80/480 mg) twice daily for 3 days. Mild adverse events occurred in six participants (four ruxolitinib; two placebo). The combination of artemether-lumefantrine and ruxolitinib was well tolerated, with adverse events and pharmacokinetics consistent with the known profiles of both drugs. The incidence of adverse events and artemether, dihydroartemisinin (the major active metabolite of artemether), and lumefantrine exposure were not affected by ruxolitinib coadministration. Ruxolitinib coadministration resulted in a 3-fold-greater pSTAT3 inhibition compared to placebo (geometric mean ratio = 3.01 [90% confidence interval = 2.14 to 4.24]), with a direct and predictable relationship between ruxolitinib plasma concentrations and %pSTAT3 inhibition. This study supports the investigation of the combination of artemether-lumefantrine and ruxolitinib in healthy volunteers infected with Plasmodium falciparum malaria. (This study has been registered at ClinicalTrials.gov under registration no. NCT04456634.).

Do Side Effects to the Primary COVID-19 Vaccine Reduce Intentions for a COVID-19 Vaccine Booster?

BACKGROUND: Vaccines are being administered worldwide to combat the COVID-19 pandemic. Vaccine boosters are essential for maintaining immunity and protecting against virus variants. The side effects of the primary COVID-19 vaccine (e.g., headache, nausea), however, could reduce intentions to repeat the vaccination experience, thereby hindering global inoculation efforts. PURPOSE: The aim of this research was to test whether side effects of a primary COVID-19 vaccine relate to reduced intentions to receive a COVID-19 booster. The secondary aim was to test whether psychological and demographic factors predict booster intentions. METHODS: Secondary data analyses were conducted on a U.S. national sample of 551 individuals recruited through the online platform Prolific. Key measures in the dataset were side effects reported from a primary COVID-19 vaccination and subsequent intentions to receive a booster vaccine. Psychological and demographic variables that predicted primary vaccination intentions in prior studies were also measured. RESULTS: Booster intentions were high. COVID-19 booster vaccine intentions were uncorrelated with the number of side effects, intensity of side effects, or occurrence of an intense side effect from the primary COVID-19 vaccine. Correlational and regression analyses indicated intentions for a booster vaccination increased with positive vaccination attitudes, trust in vaccine development, worry about the COVID-19 pandemic, low concern over vaccine side effects, and democratic political party affiliation. CONCLUSIONS: Side effects of a primary COVID-19 vaccine were not directly associated with lower intentions to receive a booster of the COVID-19 vaccine early in the pandemic. However, many variables that predict primary vaccination intentions also predict booster intentions.

Quantification of Tafenoquine and 5,6-Orthoquinone Tafenoquine by UHPLC-MS/MS in Blood, Plasma, and Urine, and Application to a Pharmacokinetic Study.

Analytical methods for the quantification of the new 8-aminoquinoline antimalarial tafenoquine (TQ) in human blood, plasma and urine, and the 5,6-orthoquinone tafenoquine metabolite (5,6-OQTQ) in human plasma and urine have been validated. The procedure involved acetonitrile extraction of samples followed by ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Chromatography was performed using a Waters Atlantis T3 column with a gradient of 0.1% formic acid and acetonitrile at a flow rate of 0.5 mL per minute for blood and plasma. Urine analysis was the same but with methanol containing 0.1% formic acid replacing acetonitrile mobile phase. The calibration range for TQ and 5,6-OQTQ in plasma was 1 to 1200 ng/mL, and in urine was 10 to 1000 ng/mL. Blood calibration range for TQ was 1 to 1200 ng/mL. Blood could not be validated for 5,6-OQTQ due to significant signal suppression. The inter-assay precision (coefficient of variation %) was 9.9% for TQ at 1 ng/mL in blood (n = 14) and 8.2% for TQ and 7.1% for 5,6-OQTQ at 1 ng/mL in plasma (n = 14). For urine, the inter-assay precision was 8.2% for TQ and 6.4% for 5,6-OQTQ at 10 ng/mL (n = 14). TQ and 5,6-OQTQ are stable in blood, plasma and urine for at least three months at both -80 °C and -20 °C. Once validated, the analytical methods were applied to samples collected from healthy volunteers who were experimentally infected with Plasmodium falciparum to evaluate the blood stage antimalarial activity of TQ and to determine the therapeutic dose estimates for TQ, the full details of which will be published elsewhere. In this study, the measurement of TQ and 5,6-OQTQ concentrations in samples from one of the four cohorts of participants is reported. Interestingly, TQ urine concentrations were proportional to parasite recrudescence times post dosing To our knowledge, this is the first description of a fully validated method for the measurement of TQ and 5,6-OQTQ quantification in urine.

The psychological impact of quarantine and how to reduce it: rapid review of the evidence.

The December, 2019 coronavirus disease outbreak has seen many countries ask people who have potentially come into contact with the infection to isolate themselves at home or in a dedicated quarantine facility. Decisions on how to apply quarantine should be based on the best available evidence. We did a Review of the psychological impact of quarantine using three electronic databases. Of 3166 papers found, 24 are included in this Review. Most reviewed studies reported negative psychological effects including post-traumatic stress symptoms, confusion, and anger. Stressors included longer quarantine duration, infection fears, frustration, boredom, inadequate supplies, inadequate information, financial loss, and stigma. Some researchers have suggested long-lasting effects. In situations where quarantine is deemed necessary, officials should quarantine individuals for no longer than required, provide clear rationale for quarantine and information about protocols, and ensure sufficient supplies are provided. Appeals to altruism by reminding the public about the benefits of quarantine to wider society can be favourable.

Safety, infectivity and immunogenicity of a genetically attenuated blood-stage malaria vaccine.

BACKGROUND: There is a clear need for novel approaches to malaria vaccine development. We aimed to develop a genetically attenuated blood-stage vaccine and test its safety, infectivity, and immunogenicity in healthy volunteers. Our approach was to target the gene encoding the knob-associated histidine-rich protein (KAHRP), which is responsible for the assembly of knob structures at the infected erythrocyte surface. Knobs are required for correct display of the polymorphic adhesion ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1), a key virulence determinant encoded by a repertoire of var genes. METHODS: The gene encoding KAHRP was deleted from P. falciparum 3D7 and a master cell bank was produced in accordance with Good Manufacturing Practice. Eight malaria naïve males were intravenously inoculated (day 0) with 1800 (2 subjects), 1.8 × 105 (2 subjects), or 3 × 106 viable parasites (4 subjects). Parasitemia was measured using qPCR; immunogenicity was determined using standard assays. Parasites were rescued into culture for in vitro analyses (genome sequencing, cytoadhesion assays, scanning electron microscopy, var gene expression). RESULTS: None of the subjects who were administered with 1800 or 1.8 × 105 parasites developed parasitemia; 3/4 subjects administered 3× 106 parasites developed significant parasitemia, first detected on days 13, 18, and 22. One of these three subjects developed symptoms of malaria simultaneously with influenza B (day 17; 14,022 parasites/mL); one subject developed mild symptoms on day 28 (19,956 parasites/mL); and one subject remained asymptomatic up to day 35 (5046 parasites/mL). Parasitemia rapidly cleared with artemether/lumefantrine. Parasitemia induced a parasite-specific antibody and cell-mediated immune response. Parasites cultured ex vivo exhibited genotypic and phenotypic properties similar to inoculated parasites, although the var gene expression profile changed during growth in vivo. CONCLUSIONS: This study represents the first clinical investigation of a genetically attenuated blood-stage human malaria vaccine. A P. falciparum 3D7 kahrp- strain was tested in vivo and found to be immunogenic but can lead to patent parasitemia at high doses. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (number: ACTRN12617000824369 ; date: 06 June 2017).

Development and evaluation of a new Plasmodium falciparum 3D7 blood stage malaria cell bank for use in malaria volunteer infection studies.

BACKGROUND: New anti-malarial therapeutics are required to counter the threat of increasing drug resistance. Malaria volunteer infection studies (VIS), particularly the induced blood stage malaria (IBSM) model, play a key role in accelerating anti-malarial drug development. Supply of the reference 3D7-V2 Plasmodium falciparum malaria cell bank (MCB) is limited. This study aimed to develop a new MCB, and compare the safety and infectivity of this MCB with the existing 3D7-V2 MCB, in a VIS. A second bank (3D7-V1) developed in 1995 was also evaluated. METHODS: The 3D7-V2 MCB was expanded in vitro using a bioreactor to produce a new MCB designated 3D7-MBE-008. This bank and 3D7-V1 were then evaluated using the IBSM model, where healthy participants were intravenously inoculated with blood-stage parasites. Participants were treated with artemether-lumefantrine when parasitaemia or clinical thresholds were reached. Safety, infectivity and parasite growth and clearance were evaluated. RESULTS: The in vitro expansion of 3D7-V2 produced 200 vials of the 3D7-MBE-008 MCB, with a parasitaemia of 4.3%. This compares to 0.1% in the existing 3D7-V2 MCB, and < 0.01% in the 3D7-V1 MCB. All four participants (two per MCB) developed detectable P. falciparum infection after inoculation with approximately 2800 parasites. For the 3D7-MBE-008 MCB, the parasite multiplication rate of 48 h (PMR48) using non-linear mixed effects modelling was 34.6 (95% CI 18.5-64.6), similar to the parental 3D7-V2 line; parasitaemia in both participants exceeded 10,000/mL by day 8. Growth of the 3D7-V1 was slower (PMR48 of 11.5 [95% CI 8.5-15.6]), with parasitaemia exceeding 10,000 parasites/mL on days 10 and 8.5. Rapid parasite clearance followed artemether-lumefantrine treatment in all four participants, with clearance half-lives of 4.01 and 4.06 (weighted mean 4.04 [95% CI 3.61-4.57]) hours for 3D7-MBE-008 and 4.11 and 4.52 (weighted mean 4.31 [95% CI 4.16-4.47]) hours for 3D7-V1. A total of 59 adverse events occurred; most were of mild severity with three being severe in the 3D7-MBE-008 study. CONCLUSION: The safety, growth and clearance profiles of the expanded 3D7-MBE-008 MCB closely resemble that of its parent, indicating its suitability for future studies. TRIAL REGISTRATION: Australian New Zealand Clinical Trials registry numbers: P3487 (3D7-V1): ACTRN12619001085167. P3491 (3D7-MBE-008): ACTRN12619001079134.

Predicting Expectations of Side-Effects for Those Which Are Warned Versus Not Warned About in Patient Information Leaflets.

BACKGROUND: Research investigating predictors of side-effect expectations is disparate and largely based on hypothetical vignettes. PURPOSE: To carry out a secondary analysis of a randomized controlled trial and investigate the predictors of side-effect expectations for side-effects that were, or were not, warned about. METHODS: Two hundred and three healthy adults completed measures concerning demographics, psychological factors, baseline symptoms, and medication-related beliefs before reading one of two types of patient information leaflet (PIL) (standard or positively framed PIL) for a sham medication and asking them about their side-effect expectations. Associations between these measures and side-effect expectations whilst controlling for the PIL received were assessed using regression analyses. RESULTS: 82.8% of participants expected side-effects that were warned about in the PIL, and 29.1% expected side-effects that were not warned about. Participants who were younger, from White backgrounds, less optimistic, experienced increased anxiety and received the standard PIL were more likely to expect side-effects that were warned about. Those with higher beliefs about medicine overuse and lower trust in medicine development were more likely to expect side-effects that were not warned about. Higher somatization, baseline symptoms, modern health worries scores, and lower trust in pharmaceutical companies were associated with increased expectations for all side-effects. The results suggest we can not only rely on altering side-effect risk communication to reduce side-effect expectations and therefore nocebo effects. We must also consider patients' beliefs about trust in medicines. More work is needed to investigate this in a patientsample in which the medication is known to them.

TIDieR-Placebo: A guide and checklist for reporting placebo and sham controls.

BACKGROUND: Placebo or sham controls are the standard against which the benefits and harms of many active interventions are measured. Whilst the components and the method of their delivery have been shown to affect study outcomes, placebo and sham controls are rarely reported and often not matched to those of the active comparator. This can influence how beneficial or harmful the active intervention appears to be. Without adequate descriptions of placebo or sham controls, it is difficult to interpret results about the benefits and harms of active interventions within placebo-controlled trials. To overcome this problem, we developed a checklist and guide for reporting placebo or sham interventions. METHODS AND FINDINGS: We developed an initial list of items for the checklist by surveying experts in placebo research (n = 14). Because of the diverse contexts in which placebo or sham treatments are used in clinical research, we consulted experts in trials of drugs, surgery, physiotherapy, acupuncture, and psychological interventions. We then used a multistage online Delphi process with 53 participants to determine which items were deemed to be essential. We next convened a group of experts and stakeholders (n = 16). Our main output was a modification of the existing Template for Intervention Description and Replication (TIDieR) checklist; this allows the key features of both active interventions and placebo or sham controls to be concisely summarised by researchers. The main differences between TIDieR-Placebo and the original TIDieR are the explicit requirement to describe the setting (i.e., features of the physical environment that go beyond geographic location), the need to report whether blinding was successful (when this was measured), and the need to present the description of placebo components alongside those of the active comparator. CONCLUSIONS: We encourage TIDieR-Placebo to be used alongside TIDieR to assist the reporting of placebo or sham components and the trials in which they are used.

A systematic review of factors associated with side-effect expectations from medical interventions.

BACKGROUND: Fear of side-effects can result in non-adherence to medical interventions, such as medication and chemotherapy. Side-effect expectations have been identified as strong predictors of later perception of side-effects. However, research investigating predictors of side-effect expectations is disparate. OBJECTIVE: To identify factors associated with side-effect expectations. SEARCH STRATEGY: We systematically searched Embase, Ovid MEDLINE, Global Health, PsycARTICLES, PsycINFO, Web of Science and Scopus. INCLUSION CRITERIA: Studies were included if they investigated associations between any predictive factor and expectations of side-effects from any medical intervention. DATA EXTRACTION AND SYNTHESIS: We extracted information about participant characteristics, medication, rates of side-effects expected and predictors of side-effect expectations. Data were narratively synthesized. MAIN RESULTS: We identified sixty-four citations, reporting on seventy-two studies. Predictors fell into five categories: personal characteristics, clinical characteristics, psychological traits and state, presentation format of information, and information sources used. Using verbal risk descriptors (eg 'common') compared to numerical descriptors (eg percentages), having lower quality of life or well-being, and currently experiencing symptoms were associated with increased side-effect expectations. DISCUSSION AND CONCLUSIONS: Decreasing unrealistic side-effect expectations may lead to decreased experience of side-effects and increased adherence to medical interventions. Widespread communications about medical interventions should describe the incidence of side-effects numerically. Evidence suggests that clinicians should take particular care with patients with lower quality of life, who are currently experiencing symptoms and who have previously experienced symptoms from treatment. Further research should investigate different clinical populations and aim to quantify the impact of the media and social media on side-effect expectations.

The impact of unplanned school closure on children's social contact: rapid evidence review.

BackgroundEmergency school closures are often used as public health interventions during infectious disease outbreaks to minimise the spread of infection. However, if children continue mixing with others outside the home during closures, the effect of these measures may be limited.AimThis review aimed to summarise existing literature on children's activities and contacts made outside the home during unplanned school closures.MethodsIn February 2020, we searched four databases, MEDLINE, PsycInfo, Embase and Web of Science, from inception to 5 February 2020 for papers published in English or Italian in peer-reviewed journals reporting on primary research exploring children's social activities during unplanned school closures. Main findings were extracted.ResultsA total of 3,343 citations were screened and 19 included in the review. Activities and social contacts appeared to decrease during closures, but contact remained common. All studies reported children leaving the home or being cared for by non-household members. There was some evidence that older child age (two studies) and parental disagreement (two studies) with closure were predictive of children leaving the home, and mixed evidence regarding the relationship between infection status and such. Parental agreement with closure was generally high, but some disagreed because of perceived low risk of infection and issues regarding childcare and financial impact.ConclusionEvidence suggests that many children continue to leave home and mix with others during school closures despite public health recommendations to avoid social contact. This review of behaviour during unplanned school closures could be used to improve infectious disease modelling.

Research fatigue in COVID-19 pandemic and post-disaster research: Causes, consequences and recommendations.

PURPOSE: Research fatigue occurs when an individual or population of interest tires of engaging with research, consequently avoiding further participation. This paper considers research fatigue in the context of the current COVID-19 pandemic, to identify contributory factors and possible solutions for future post-disaster research. METHODOLOGY: We draw on examples from the literature and our own observations from the recruitment and data collection phases of qualitative and quantitative studies, to provide an overview of possible research fatigue in the current COVID-19 pandemic, with implications for future post-disaster research. FINDINGS: People affected by disasters sometimes receive multiple requests for study participation by separate teams who may not necessarily be coordinating their work. Not keeping participants informed of the research process or outcomes can lead to disillusionment. Being overburdened with too many research requests and failing to see any subsequent changes following participation may cause individuals to experience research fatigue. ORIGINALITY: Guidelines for researchers wishing to reduce the occurrence of research fatigue include ensuring greater transparency within research; sharing of results; and using oversight or gatekeeper bodies to aid coordination. Failure to restrict the number of times that people are asked to participate in studies risks poor participation rates. This can subsequently affect the quality of information with which to inform policy-makers and protect the health of the public during the COVID-19 pandemic or other public health disasters/emergencies.

Inadequate description of placebo and sham controls in a systematic review of recent trials.

BACKGROUND: Poorly described placebo/sham controls make it difficult to appraise active intervention benefits and harms. The 12-item Template for Intervention Description and Replication (TIDieR) checklist was developed to improve the reporting of active interventions. The extent to which TIDieR has been used to improve description of placebo or sham control is not known. MATERIALS AND METHODS: We systematically identified and examined all placebo/sham-controlled randomised trials published in 2018 in the top six general medical journals. We reported how many of the TIDieR checklist items were used to describe the placebo/sham control(s). We supplemented this with a sample of 100 placebo/sham-controlled trials from any journal and searched Google Scholar to identify placebo/sham-controlled trials citing TIDieR. RESULTS: We identified 94 placebo/sham-controlled trials published in the top journals in 2018. None reported using TIDieR, and none reported placebo or sham components completely. On average eight TIDieR items were addressed, with placebo/sham control name (100%) and when and how much was administered (97.9%) most commonly reported. Some items (rationale, 8.5%, whether there were modifications, 25.5%) were less often reported. In our sample of less well-cited journals, reporting was poorer (average of six items) and followed a similar pattern. Since TIDieR's first publication, six placebo-controlled trials have cited it according to Google Scholar. Two of these used the checklist to describe placebo controls; neither one completely desribed the placebo intervention. CONCLUSIONS: Placebo and sham controls are poorly described within randomised trials, and TIDieR is rarely used to guide these descriptions. We recommend developing guidelines to promote better descriptions of placebo/sham control components within clinical trials.

Positively Framed Risk Information in Patient Information Leaflets Reduces Side Effect Reporting: A Double-Blind Randomized Controlled Trial.

Background: Many medication side effects are the result of a psychologically mediated "nocebo effect," triggered by negative expectations. Purpose: This study investigated if changing how side effect information is framed in patient information leaflets (PILs) reduces symptom reporting. Methods: A total of 203 healthy volunteers aged 18 or over were recruited from December 1, 2015 to December 5, 2016 into a double-blind randomized controlled trial carried out at the Clinical Research Facility at King's College Hospital. King's Clinical Trial Unit randomized participants (stratified by gender) to receive a PIL for "a well-known tablet available without prescription" that used standard side effect risk information (e.g., "Common, 1 in 10 people will be affected") or positively framed wording (e.g., "Uncommon, 90% of people will not be affected"). After reading their PIL, participants took the tablet (a placebo) and completed symptom reports 1 hr later. The main outcomes included the number of participants who attributed symptoms to the tablet, and the number and severity of attributed symptoms. Results: A total of 101 participants were assigned the standard PIL and 102 the positive framed PIL. Significantly more standard PIL participants attributed symptoms to the tablet (n = 55, 54.5%) compared to positively framed PIL participants (n = 40, 39.2%), odds ratio (OR) = 0.66, 95% CI: 0.46-0.93. Positive framing did not significantly reduce the total number (p = .148) or severity (p = .149) of symptoms attributed to the tablet. Conclusion: Positive framing reduced the likelihood of participants attributing nocebo-induced side effects to the tablet. Work is needed to assess the effectiveness in a patient population. Clinical Trial information: ISRCTN47470030.

How does the side-effect information in patient information leaflets influence peoples' side-effect expectations? A cross-sectional national survey of 18- to 65-year-olds in England.

OBJECTIVES: To establish how the terms recommended by the European Commission to describe side-effect risk in patient information leaflets (PILs) influences expectations of side-effects and to identify factors associated with these side-effect expectations. DESIGN: A cross-sectional online survey was carried out by a market research company. SETTING: Data were collected in England between 18th March and 1st April 2016. PARTICIPANTS: A total of 1003 adults aged between 18 and 65. MAIN OUTCOME MEASURES: Self-reported expectation that the described side-effects would affect participants if they took the medicine, measured on a likelihood scale from 1 (very unlikely) to 5 (very likely). RESULTS: Participants formed high expectations of side-effects for "very common" and "common" side-effects, with 51.9% and 45.0% of participants rating these as "very likely" or "likely" to happen to them, respectively. This fell to 8.1% for "uncommon," 5.8% for "rare" and 4.1% for "very rare." For each descriptor, higher expectations of side-effects were more associated with women or being from an ethnic minority, or having less education, a household illness, high perceived sensitivity to medicines or negative beliefs about medicines. DISCUSSION: The current use of verbal descriptors to communicate side-effect risk in PILs leads to high side-effect expectations. These expectations could contribute to nocebo-induced medication side-effects experienced by patients. Additional work is required to identify ways to improve the way risk information is conveyed in PILs.

miR-331-3p regulates expression of neuropilin-2 in glioblastoma.

Aberrant expression of microRNAs (miRNAs), a class of small non-coding regulatory RNAs, has been implicated in the development and progression of high-grade gliomas. However, the precise mechanistic role of many miRNAs in this disease remains unclear. Here, we investigate the functional role of miR-331-3p in glioblastoma multiforme (GBM). We found that miR-331-3p expression in GBM cell lines is significantly lower than in normal brain, and that transient overexpression of miR-331-3p inhibits GBM cell line proliferation and clonogenic growth, suggesting a possible tumor suppressor role for miR-331-3p in this system. Bioinformatics analysis identified neuropilin-2 (NRP-2) as a putative target of miR-331-3p. Using transfection studies, we validated NRP-2 mRNA as a target of miR-331-3p in GBM cell lines, and show that NRP-2 expression is regulated by miR-331-3p. RNA interference (RNAi) to inhibit NRP-2 expression in vitro decreased the growth and clonogenic growth of GBM cell lines, providing further support for an oncogenic role for NRP-2 in high-grade gliomas. We also show that miR-331-3p inhibits GBM cell migration, an effect due in part to reduced NRP-2 expression. Finally, we identified a significant inverse correlation between miR-331-3p and NRP-2 expression in The Cancer Genome Atlas GBM cohort of 491 patients. Together, our results suggest that a loss of miR-331-3p expression contributes to GBM development and progression, at least in part via upregulating NRP-2 expression and increasing cell proliferation and clonogenic growth.

Characteristics and prenatal care utilisation of Romanian pregnant women.

OBJECTIVE: To describe the degree to which Romanian women access free prenatal care services, and to describe the demographic profile of women who are at risk for underutilisation. METHODS: Secondary data (n = 914) were taken from a large, nationally representative sample of Romanian mothers and children (N = 2117). Kotelchuck's Adequacy of Prenatal Care Utilisation Index was used to measure the adequacy of prenatal care. RESULTS: Seventy-eight percent of mothers underutilised prenatal care services. Those who did so to the greatest degree were likely to be young, members of an ethnic minority, poor, uneducated, and rural. Conversely, those who utilised care to the greatest degree were likely to be older, members of the ethnic majority, wealthy, educated, and city dwelling. CONCLUSION: Despite the fact that many of the risk factors for underutilisation in this sample were similar to those found elsewhere in Europe and the developed world, these findings illustrate the worrisome magnitude of the problem in Romania, particularly among women with low levels of income and educational attainment. Future studies should examine factors that contribute to underutilisation, whether it corresponds to negative health outcomes, and whether targeted social interventions and outreach could help improve care.