A single blinded, phase IV, adaptive randomised control trial to evaluate the safety of coadministration of seasonal influenza and COVID-19 vaccines (The FluVID study).

OBJECTIVES: We evaluated the frequency of moderate and severe adverse events following coadministration of seasonal influenza vaccine (SIV) versus placebo with COVID-19 vaccines among adults to support practice guidelines. METHODS: FluVID is a participant-blinded, phase IV, randomised control trial. On the same day as the participant's scheduled COVID-19 vaccine, participants were randomised to receive SIV or saline placebo; those assigned placebo at visit one then received SIV a week later, and vice versa. Self-reported adverse events were collected daily for seven days following each visit. The primary endpoint was any solicited adverse event of at least moderate severity occurring up to seven days following receipt of SIV or placebo. This was modelled using a Bayesian logistic regression model. Analyses were performed by COVID-19 vaccine type and dose number. RESULTS: Overall, 248 participants were enrolled; of these, 195 had received BNT162b2 and 53 had received mRNA1273 COVID-19 vaccines according to national guidelines. After randomisation, 119 were assigned to receive SIV and 129 were assigned to receive placebo at visit one. Adverse events were most frequently reported as mild (grade 1) in nature. Among 142 BNT162b2 booster dose one and 43 BNT162b2 booster dose two recipients, the posterior median risk difference for moderate/severe adverse events following SIV versus placebo was 13% (95% credible interval [CrI] -0.03 to 0.27) and 13% (95%CrI -0.37 to 0.12), respectively. Among 18 mRNA1273 booster dose one and 35 mRNA1273 booster dose two recipients, the posterior median risk difference of moderate/severe adverse events following influenza vaccine versus placebo was 6% (95%CrI -0.29 to 0.41) and -4% (95%CrI -0.30 to 0.23), respectively. CONCLUSION: Adverse events following SIV and COVID-19 co-administration were generally mild and occurred with similar frequency to events following COVID-19 vaccine alone. We found no evidence to justify routine separation of SIV and COVID-19 vaccine doses. CLINICAL TRIAL REGISTRATION: ACTRN12621001063808.

Predicted aquatic and human health risks associated with the presence of metals in the Syr Darya and Shardara Reservoir, Kazakhstan.

Due to the decline of the Aral Sea fishery and recent efforts to expand the fisheries sector in Kazakhstan for both local consumption and global export, there is a need to sustain other fisheries in the area, including the Shardara Reservoir, which lies in the Syr Darya basin. Metals are present in the Syr Darya; yet, their impacts on fishery and consumer health remain unclear. Thus, the objectives of this study were to evaluate: 1) the potential impacts of metals on Syr Darya basin fish and 2) the human health risks posed by consumption of Shardara Reservoir fish. The health of the fishery was assessed by comparing surface water metal concentrations to maximum permissible concentrations (MPCs), calculating water quality index (WQI) and degree of contamination (Cd) values, and evaluating gene expression biomarker responses in wild-caught roach (Rutilus rutilus). To assess the risk to consumers, metal concentrations in roach were used to calculate hazard quotients (HQs) and hazard indices (HIs). Water concentrations of Cu, Fe, Mn, Se, Sr and V exceeded MPCs and all sites were classified as highly polluted based upon WQI and Cd values. This, along with site-specific differences in the expression of genes associated with xenobiotic metabolism and oxidative stress in roach, indicates potential risks to the fishery. Though all HQs and HIs were below 1 indicating a lack of significant risk to consumers, Pb levels in roach exceeded MPCs for safe consumption indicating a potential risk. Given the potential risks to the fishery and consumers, the development of pollution monitoring and management programs are warranted. The work presented here provides initial monitoring data that can be used to aid such efforts and also underscores the need to identify environmental stressors that may thwart the anticipated growth of fisheries in this region.

Concussion symptoms experienced during driving may influence driving habits.

Objective: To examine the symptoms experienced and the change in driving habits in individuals with concussion.Materials and methods: A survey was created by a team of rehabilitation professionals who see persons with concussion in their clinics. The survey captured demographics, mechanism of injury, date of injury, symptoms experienced during driving, if drivers felt safe when driving, and changes in driving habits since the concussion. Non-parametric tests were used to compare symptoms experienced and driving habits across three groups which were created based on time since injury.Results: Of the 140 participants, 74% (104/140) had resumed driving after concussion; of these 27% (28/104) reported that they felt unsafe while driving. Forty-four per cent (46/104) experienced symptoms while driving, of which headache, and difficulty concentrating were the most common symptoms experienced throughout the concussion spectrum (acute to chronic phase). Most drivers (78/104, 75%) with concussion had changed their driving habits by driving less often and shorter distances, and by avoiding nighttime driving and heavy traffic areas.Conclusions: Headache and concentration problems were experienced by drivers regardless of the time since injury. Most drivers had made changes to their driving habits. Clinicians should consider the symptom burden patients experience and discuss driving restrictions to ensure driving safety.

Reflective debrief and the social space: offload, refuel, and stay on course.

Relentless workloads are birthing unprecedented levels of burnout, mental ill health, substance misuse, and suicide amongst clinical staff working in the NHS. The consequent epidemic of sickness absence, early retirement, and poor staff retention means the workforce gap is widening at an alarming rate within the caring professions. The clarion call rings out loud, clear, and with urgency for organisational engagement in preventative measures to invest in its human capital. Interventions for increasing clinician wellbeing and resilience must encompass strategies at the personal level, at peer groups and teams, right through to the level of the culture and practices - the "operating system" - of the whole organisation. In hospitals across the nation, where the pervading environment is one of "lack" - time, space, thanks, morale - significant casualties are a sense of "community at work" and sanctioned time for reflective practice. Relaxed, reflective group debrief cultivates relational connection, enables off-loading of the burdens associated with caring and guides reflective "work on work". Clinicians attending reflective groups appreciate the opportunity for a "space to breathe", for self-reflection, mindfulness, and self-care, whilst gaining professional robustness and a sense of value and team. Could the low-cost model of monthly, facilitated "clinician wellbeing and debrief" gatherings and the provision of "pop-up" departmental café spaces, as pioneered in Cambridge, UK, significantly enrich our healthcare system's culture of "lack"?

A review of ecological effects and environmental fate of illicit drugs in aquatic ecosystems.

Although illicit drugs are detected in surface waters throughout the world, their environmental fate and ecological effects are not well understood. Many illicit drugs and their breakdown products have been detected in surface waters and temporal and spatial variability in use translates into "hot spots and hot moments" of occurrence. Illicit drug occurrence in regions of production and use and areas with insufficient wastewater treatment are not well studied and should be targeted for further study. Evidence suggests that illicit drugs may not be persistent, as their half-lives are relatively short, but may exhibit "pseudo-persistence" wherein continual use results in persistent occurrence. We reviewed the literature on the ecological effects of these compounds on aquatic organisms and although research is limited, a wide array of aquatic organisms, including bacteria, algae, invertebrates, and fishes, have receptors that make them potentially sensitive to these compounds. In summary, illicit drugs occur in surface waters and aquatic organisms may be affected by these compounds; research is needed that focuses on concentrations of illicit drugs in areas of production and high use, environmental fate of these compounds, and effects of these compounds on aquatic ecosystems at the concentrations that typically occur in the environment.

Lamotrigine monotherapy in children.

The effectiveness of lamotrigine as a monotherapeutic agent for a variety of pediatric epilepsies was reviewed retrospectively. Children were categorized as having focal vs generalized epilepsy and according to whether they were antiepileptic drug naive or drug exposed. Data collected included dosages, side effects, length of follow-up, number of prior drugs, and treatment response. Treatment was considered successful if the patient was seizure free for 6 months or more. Eighty-three children were identified (average age = 8.7 years); 43 had focal epilepsy, 32 had generalized epilepsy, and eight were not classified. Twenty-nine patients were classified as having specific syndromes. Fourteen patients were drug naive. The median follow-up period was 8 months (mean = 8.5). Overall, 45% were seizure free, 44% with focal epilepsy and 36% with generalized epilepsy. All children with juvenile myoclonic epilepsy and benign rolandic epilepsy of childhood were seizure free, although not all had been treated for at least 6 months. One third of drug-naive patients were seizure free. Rash was the most common side effect and was reported in five patients (6%); two patients discontinued the drug. None had Stevens-Johnson syndrome. One quarter of children experienced nonquantifiable improvements, namely increased alertness and improved behavior regardless of seizure control. Lamotrigine is effective as a monotherapeutic agent in children for both focal and generalized epilepsies. Side effects are relatively uncommon. Lamotrigine may be an effective firstline agent.

Rhinovirus 2A proteinase mediated stimulation of rhinovirus RNA translation is additive to the stimulation effected by cellular RNA binding proteins.

The internal ribosome entry site (IRES) of enteroviruses, and especially human rhinoviruses (HRV), functions very inefficiently in rabbit reticulocyte lysates, but can be stimulated by addition of HeLa cell extracts. Two HeLa cell activities have been identified: the A-type activity is due to polypyrimidine tract binding protein and the B-type to unr. In addition HRV and enterovirus IRES function requires a third RNA binding protein, poly(rC) binding protein 2, but this is present in reticulocyte lysates in non-limiting amounts. IRES activity can also be stimulated by the cleavage of initiation factor eIF4G mediated by either HRV 2A protease, or foot-and-mouth disease virus (FMDV) L protease. This raises the question of whether this stimulation is independent of that effected by the three RNA binding proteins, or whether cleaved eIF4G functionally mimics one or more of these proteins. It is shown here that the stimulation of HRV IRES activity resulting from cleavage of eIF4G is additive with the stimulation effected by HeLa cell A- and B-type activities. It is proposed that the role of the RNA binding proteins is to maintain or attain the appropriate 3-dimensional structure of the IRES RNA element, whereas the function of eIF4G is to deliver the 40S ribosomal subunit to the correct site on the IRES, a function which, for reasons not yet fully understood, is fulfilled more efficiently by the C-terminal cleavage product of eIF4G than by the intact factor.

Polypyrimidine-tract binding protein (PTB) is necessary, but not sufficient, for efficient internal initiation of translation of human rhinovirus-2 RNA.

Initiation of translation of the animal picornavirus RNAs is via a mechanism of direct internal ribosome entry, which requires a substantial segment of the viral 5'-untranslated region, generally known as the IRES (for "internal ribosome entry site"). Because, however, translation of the RNAs of members of the enterovirus, and more especially, the rhinovirus subgroups of the Picornaviridae is restricted in the reticulocyte lysate system, but is greatly stimulated by the addition of HeLa cell extracts, the implication is that, in these cases, internal initiation also requires cellular trans-acting factors that are more abundant in HeLa cell extracts than in rabbit reticulocytes. This was used as the basis of a functional assay for the purification of the HeLa cell factors required for translation dependent on the human rhinovirus-2 (HRV) IRES. There are two such HeLa cell factors separable by ion-exchange chromatography, each of which is individually active in the assay, although their combined effect is synergistic. One of these activities is shown to be polypyrimidine-tract binding protein (PTB) on the grounds that (1) the activity copurifies to homogeneity with PTB and (2) recombinant PTB expressed in Escherichia coli stimulates HRV IRES-dependent translation with a specific activity similar to that of the purified HeLa cell factor. Furthermore, it is shown that recombinant PTB also stimulates the translation of RNAs bearing the poliovirus type 1 (Mahoney) IRES.

unr, a cellular cytoplasmic RNA-binding protein with five cold-shock domains, is required for internal initiation of translation of human rhinovirus RNA.

Initiation of translation of the animal picornavirus RNAs occurs via a mechanism of direct ribosome entry, which requires a segment of the 5' UTR of the RNA, known as the internal ribosome entry site (IRES). In addition, translation of the enterovirus and rhinovirus (HRV) subgroups requires cellular trans-acting factors that are absent from, or limiting in rabbit reticulocytes, but are more abundant in HeLa cell extracts. It has been shown previously that HeLa cells contain two separable activities, each of which independently stimulates HRV IRES-dependent translation when used to supplement reticulocyte lysate; one of these activities was identified as polypyrimidine tract-binding protein (PTB). Here, the purification of the second activity is achieved by use of an RNA-affinity column based on the HRV 5' UTR. It comprises two components: a 38-kD protein (p38), which is a novel member of the GH-WD repeat protein family and has no intrinsic RNA-binding activity; and a 96- to 97-kD protein doublet, which was identified as unr, an RNA-binding protein with five cold-shock domains. Coimmunoprecipitation with antibodies against either protein shows that the two proteins interact with each other, and thus p38 is named unrip (unr-interacting protein). Recombinant unr acts synergistically with recombinant PTB to stimulate translation dependent on the rhinovirus IRES. In contrast, unr did not significantly augment the PTB-dependent stimulation of poliovirus IRES activity.

A review of the newer antiepileptic drugs and the ketogenic diet.

Since 1994, three new antiepileptic drugs, felbamate, lamotrigene, and gabapentin, have been released for the treatment of epilepsy. The present paper provides an overview of these three drugs and reviews their potential uses in pediatric epilepsy even though felbamate is the only one with an approved use in children. Topiramate and vigabatrin, which are under investigation, are briefly reviewed. In addition, a discussion of the ketogenic diet is included because of its recent publicity. Patient examples included provide clinical illustrations for the reader.

Direct evidence that polypyrimidine tract binding protein (PTB) is essential for internal initiation of translation of encephalomyocarditis virus RNA.

The requirement of PTB, polypyrimidine tract binding protein, for internal initiation of translation has been tested using an RNA affinity column to deplete rabbit reticulocyte lysates of PTB. The affinity column was prepared by coupling CNBr-activated Sepharose with the segment of the 5'-untranslated region of encephalomyocarditis virus (EMCV) RNA previously shown to bind PTB. Lysates passed through this column were devoid of PTB, and were incapable of internal initiation of translation dependent on the EMCV 5'-untranslated region, while retaining the capacity for translation dependent on ribosome scanning. Full activity for internal initiation was restored by the addition of recombinant PTB at the physiologically relevant concentration of about 5 micrograms/mL. When various PTB deletion mutants were tested, it was found that this activity required virtually the full-length protein. Thus, PTB is an essential protein for internal initiation promoted by the EMCV 5'-untranslated region. However, the PTB-depleted lysate retained the capacity for internal initiation promoted by the 5'-untranslated regions of another cardiovirus, Theiler's murine encephalomyelitis virus, and of the unrelated hepatitis C virus, and in neither case did addition of recombinant PTB stimulate internal initiation. Therefore, PTB is not a universal internal initiation factor that is indispensable in every case of internal ribosome entry.

Age-cohort differences in treating symptoms of mental illness: a process approach.

This study examines age-cohort differences in conceptually organizing, observing, and responding to unclustered symptoms of mental illness. Older (M = 70.8) and younger (M = 19.9) adults sorted symptoms of depression, schizophrenia, and age-associated changes into similarity groupings. Hierarchical cluster analysis showed that both older and younger adults sorted the statements similarly, although labels given for depressive symptoms differed across groups. Participants then reported which symptoms they had observed within their families and listed what actions were taken. Age groups showed significant differences in symptom reporting, with older individuals observing depressive symptoms less frequently. There were small differences in the kinds of actions reported. These results suggest that differences in help-seeking behavior for mental illness may be explained by differences in the way symptoms are observed by younger and older cohorts.

The influence of viral coding sequences on the efficiency of internal initiation of translation of cardiovirus RNAs.

Since internal initiation of translation of cardiovirus RNAs requires the approximately 450-nt segment of the viral genome immediately upstream of the authentic initiation codon for viral polyprotein synthesis, the question arises as to whether the immediately adjacent sequences, the start of the polyprotein coding region, also influence the efficiency of internal initiation. Therefore, a variety of constructs derived from encephalomyocarditis virus and Theiler's murine encephalomyelitis virus retaining various lengths of viral coding sequence were translated in rabbit reticulocyte lysates. Efficient internal initiation showed no requirement specifically for viral coding sequences, but on the other hand certain motifs, notably G-rich sequences, located immediately downstream of the initiation codon were highly inhibitory. These results suggest a possible explanation for the evolution of cardiovirus polyproteins lacking N-terminal myristylation signals and are also pertinent to the design of constructs in which the cardiovirus internal ribosome entry signal is used to drive the expression of a reporter cistron.

Use of a regenerable immobilized second antibody to determine azidothymidine in a flow system.

A regenerable immobilized second-antibody reactor was used to measure azidothymidine (AZT) by competitive enzyme immunoassay in a flow system. The immobilized antibody was regenerated 4 times with little loss of immunospecificity. A residual enzymatic activity of about 7% of the total response was obtained with horseradish peroxidase as label. AZT was measured below the nanomolar level by allowing competition to proceed for about 2 min. A limit of detection of 6.57 x 10(-11) +/- 1.56 x 10(-11) M AZT was obtained when the concentration of AZT-peroxidase conjugate was 0.125 ng/mL. This system was used to determined azidothymidine in Retrovir capsule with good results. In replicate measurements, RSDs of 5.51% and 2.44%, n = 6, were obtained at 7.48 x 10(-11) and 3.74 x 10(-9) M AZT, respectively.