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Functional seizures (FS) are events that resemble epileptic seizures, but are not attributed to brain pathology and are instead thought to be due to psychological factors. A small, multisite, open-label, single-arm, pilot trial of a breathing intervention known as breathing control training (BCT) found it to be safe and effective in reducing seizure frequency in FS. We propose a protocol for a study to confirm these results. A 24-week, multicentre, individually-randomised, assessor-blinded, two-arm, parallel-group efficacy and acceptability trial of BCT versus control (Befriending) in 220 participants ≥16 years of age with FS. Eligible participants will be randomly allocated to receive two sessions of either BCT or Befriending over a 4-week period. Sessions will be delivered by a respiratory physiotherapist at a clinical care site or via telehealth. They will complete assessments prior to commencing treatment and at 4, 12 and 24 weeks after their initial session of BCT/Befriending. The trial will be conducted alongside treatment as usual. An economic evaluation including cost-utility and cost-effectiveness analyses will be carried out from health sector and societal perspectives. The study has been approved by The Austin Health Human Research Ethics Committee (HREC/84335/Austin-2022) and the New Zealand Central Health and Disability Ethics Committee (2022 FULL 12324). Findings will be reported to trial participants and consumers; presented at local, national and international conferences; and disseminated by a peer-reviewed scientific journal.

Background Most patients with Posttraumatic Stress Disorder (PTSD) suffer residual symptoms following first-line treatment. Oxidative stress has been implicated in the pathophysiology of PTSD. N-acetylcysteine (NAC) is a precursor of the brain’s primary antioxidant, glutathione, and may diminish oxidative cellular damage. An 8-week pilot study of NAC in veterans with PTSD found that symptoms were significantly reduced in the NAC group compared to placebo. This study aims to confirm these findings with a larger sample in a double-blind, placebo-controlled trial to further explore the efficacy of NAC as an adjunctive therapy in treatment-resistant PTSD. Methods A multicentre, randomised, double-blind, placebo-controlled trial for adult patients who still meet criteria for PTSD following first-line treatment. The intervention comprises either NAC as a fixed dose regime of 2.7 g/day (900 mg three times daily) administered orally for 12 weeks, or placebo. Standard care for PTSD will continue in addition, including other pharmacotherapies. Detailed clinical data will be collected at randomisation and weeks 4, 8, 12, 16, and 64 post-randomisation, with self-report measures completed weekly from baseline to 16 weeks and at 64 weeks post-randomisation. Blood-based biomarkers will be collected at baseline and 12 weeks to assess the mechanism of effect. The primary outcome measure will be change in Clinician-Administered PTSD Scale for DSM-5 at 12 weeks compared with baseline. Secondary outcomes will be change in quality of life, depression, anxiety, substance use and craving, and somatic symptoms. With 126 completed participants (63 per arm), the study is powered at 80% to detect a true difference in the primary outcome measure using a two-tailed analysis with alpha = 0.05, beta = 0.2. Discussion This is the first multicentre, double blind, randomised, placebo-controlled trial of adjunctive NAC for treatment-resistant PTSD. NAC has an established safety profile, is readily available and easy to administer, and has a favourable tolerability profile, therefore making it an attractive adjunctive therapy. Inclusion of blood analyses to assess potential target engagement biomarkers of oxidative stress and neuroinflammation may help gauge the biological mechanisms of effect of NAC. Trial registration ACTRN12618001784202, retrospectively registered 31/10/2018, URL: http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376004 .

Nursing schools strive to select a diverse student population who are likely to succeed by ensuring timely student progression through the program and effective use of educational sources. The purpose of this systematic literature review is to explore the preadmission variables and selection criteria that predict student success in 4-year baccalaureate nursing programs in the U.S. Sixteen articles met the eligibility criteria, and six measures were used to define student success: (a) early academic success, particularly during the first and second year; (b) attrition; (c) timely completion of the program; (d) graduation; (e) performance in nursing courses; and (f) academic performance in other science courses. Typically, the core set of cognitive predictors used in the admission process in nursing schools were pre-nursing GPA, pre-nursing collegiate science GPA, and scores on standardized aptitude exams. This review suggests that it is challenging to isolate one single variable as the best predictor of student success; however, using a combination of variables can offer a reliable prediction method. More researchers should consider using a theoretical basis to guide their inquiry on this topic. Additionally, researchers should examine admission variables that are most relevant across programs. •Nursing schools continue using quantitative models to select nursing applicants.•The theoretical basis is imperative to inform prediction of student success.•Student demographic variables can guide establishing appropriate academic support.•Using student GPA as a selection criterion requires careful consideration.

Deep-sea vent and subsurface microorganisms are metabolically diverse and often display unique adaptive strategies that operate under elevated pressure conditions. However, because high hydrostatic pressure (HHP) laboratory cultivation has not been widely adopted, knowledge of how these microorganisms function in native high-pressure environments is limited. To explore how elevated pressures affect the metabolism and physiology of deep-sea and subsurface microorganisms, growth of a model extremophile, Archaeoglobus fulgidus (type strain VC16), was investigated up to 98 MPa in batch cultures for both chemoorganoheterotrophic and chemolithoautotrophic metabolisms. A. fulgidus is an anaerobic, hyperthermophilic sulfate reducing archaeon, first isolated from a shallow marine vent but has been commonly identified in high-pressure marine environments (to 2-4 km below sea level, 20-40 MPa), including deep-sea hydrothermal vents, deep geothermal wells, and deep oil reservoirs. In heterotrophic HHP cultivation experiments, exponential growth was observed up to 60 MPa. Cell densities were comparable from 0.1-40 MPa, while lower cell densities were observed at 50 MPa and 60 MPa and growth was inhibited at 70 MPa. A. fulgidus displayed both piezotolerance and moderate piezophily under certain heterotrophic HHP conditions. In autotrophic HHP conditions, A. fulgidus displayed piezotolerance with similar growth rates and maximum cell densities observed at up to 40 MPa and little to no growth was observed at 60 MPa. A. fulgidus biofilm production was observed in certain heterotrophic conditions from 0.1-50 MPa under HHP batch cultivation conditions due to both low calcium concentrations in the growth medium and the presence of a stainless steel needle that created a nucleation site. This suggests that biofilm production here was a response to growth medium chemistry and surface area, and was not related to the elevated pressure conditions. Here, A. fulgidus was shown to grow, and in some cases also produce biofilm, over a range of elevated pressure conditions. To the extent of our knowledge, piezotolerance to HHP for both heterotrophic and autotrophic metabolisms have not been previously measured for a single species. A. fulgidus’ metabolic plasticity and capacity for biofilm production reflects adaptive mechanisms that lend insight into how this species thrives in extreme and fluctuating environments.

Hypokalemia reportedly occurs in up to 48% of individuals cared for in outpatient settings, though it may go undetected because laboratory analyses are not routinely performed during clinic and office visits. The purpose of this study was to test the ability of a variety of noninvasive assessment parameters to predict the presence of hypokalemia, as documented by laboratory analyses. This was a descriptive study that used a convenience sample of subjects hospitalized on two telemetry units at a 500-bed community based level II institution. Among the inclusion criteria were presence of a potassium-losing diuretic, 18 years of age or greater, cognitive ability to complete four visual analog scales, neuromuscular ability to use a dynamometer in one hand, and the availability of serum potassium levels on one or more days. Seventeen subjects were followed during the course of their hospitalization and evaluated for indicators of hypokalemia on days when serum potassium levels were available. Among the variables measured were fatigue, muscle weakness, anorexia, paresthesia, bowel sounds, deep tendon reflexes, and grip strength. Although all of the potassium values were within normal range on the days of data collection, they had been below normal approximately one to two days earlier. Because of a possible time lag between potassium replacement and equilibration with cellular potassium levels, it is reasonable to assume that return to normal muscular function may not occur immediately. Therefore, the serum potassium levels were dichotomized into low normal and high normal values. Scores on muscle weakness were significantly higher in the low normal group (p = .003), as were scores on fatigue (p = .026). Similarly, dynamometer strength was significantly lower in the low normal potassium group (p = .004). It is concluded that non-laboratory indicators may prove useful in detecting abnormal physiological functioning associated with hypokalemia.

Abstract Background Pancreatic neuroendocrine tumors (pNETs) are rare cancers with outcomes determined by multiple factors including grade, stage, and clinical presentation. In this study, we aimed to determine the prognosis of patients with pNETs using a large population-based database. Materials and Methods In this population-based study, we identified patients with pNETs from the SEER 18 registry (2000-2016) using a combination of ICD-O-3 and histology codes. We calculated age-adjusted incidence rates using SEER*Stat 8.3.5. In addition, we analyzed overall survival (OS) using the Kaplan-Meier method, and investigated prognostic factors using a multivariable Cox proportional hazards model. Results A total of 8944 pNETs patients were identified. Annual incidence rates increased from 0.27 to 1.00 per 100 000. This was largely explained by an increase in number of patients diagnosed with localized disease in more recent years (2012-2016). Median OS was 68 months (95% CI [64, 73]) and 5-year OS rates in localized, regional, and metastatic disease were 83%, 67%, and 28%, respectively. There was a significant improvement in OS for patients diagnosed between 2009 and 2016 (median OS 85 months) compared with those diagnosed between 2000 and 2008 (median OS 46 months) (HR 0.66; 95% CI [0.62, 0.70]). This improvement in OS was consistent across all stages. Conclusions and Relevance This study shows a steady increase pNETs incidence with notable stage migration to earlier stages in recent years. This increase in incidence is accompanied by a significant improvement in survival across different disease stages. This study used the SEER cancer registry to research trends in the incidence and mortality rates of pancreatic neuroendocrine tumors in the United States over the past 2 decades.

In response to the COVID-19 pandemic, countries have sought to control SARS-CoV-2 transmission by restricting population movement through social distancing interventions, thus reducing the number of contacts. Mobility data represent an important proxy measure of social distancing, and here, we characterise the relationship between transmission and mobility for 52 countries around the world. Transmission significantly decreased with the initial reduction in mobility in 73% of the countries analysed, but we found evidence of decoupling of transmission and mobility following the relaxation of strict control measures for 80% of countries. For the majority of countries, mobility explained a substantial proportion of the variation in transmissibility (median adjusted R-squared: 48%, interquartile range - IQR - across countries [27–77%]). Where a change in the relationship occurred, predictive ability decreased after the relaxation; from a median adjusted R-squared of 74% (IQR across countries [49–91%]) pre-relaxation, to a median adjusted R-squared of 30% (IQR across countries [12–48%]) post-relaxation. In countries with a clear relationship between mobility and transmission both before and after strict control measures were relaxed, mobility was associated with lower transmission rates after control measures were relaxed indicating that the beneficial effects of ongoing social distancing behaviours were substantial. Social distancing policies aiming to reduce COVID-19 transmission have been reflected in reductions in human mobility. Here, the authors show that reduced mobility is correlated with decreased transmission, but that this relationship weakened over time as social distancing measures were relaxed.

Early after entry into monocytes, macrophages, dendritic cells, and resting CD4 T cells, HIV encounters a block, limiting reverse transcription (RT) of the incoming viral RNA genome. In this context, dNTP triphosphohydrolase SAM domain and HD domain-containing protein 1 (SAMHD1) has been identified as a restriction factor, lowering the concentration of dNTP substrates to limit RT. The accessory lentiviral protein X (Vpx) proteins from the major simian immunodeficiency virus of rhesus macaque, sooty mangabey, and HIV-2 (SIVsmm/SIVmac/HIV-2) lineage packaged into virions target SAMHD1 for proteasomal degradation, increase intracellular dNTP pools, and facilitate HIV cDNA synthesis. We find that virion-packaged Vpx proteins from a second SIV lineage, SIV of red-capped mangabeys or mandrills (SIVrcm/mnd-2), increased HIV infection in resting CD4 T cells, but not in macrophages, and, unexpectedly, acted in the absence of SAMHD1 degradation, dNTP pool elevation, or changes in SAMHD1 phosphorylation. Vpx rcm/mnd-2 virion incorporation resulted in a dramatic increase of HIV-1 RT intermediates and viral cDNA in infected resting CD4 T cells. These analyses also revealed a barrier limiting HIV-1 infection of resting CD4 T cells at the level of nuclear import. Single amino acid changes in the SAMHD1-degrading Vpx mac239 allowed it to enhance early postentry steps in a Vpx rcm/mnd-2–like fashion. Moreover, Vpx enhanced HIV-1 infection of SAMHD1-deficient resting CD4 T cells of a patient with Aicardi-Goutières syndrome. These results indicate that Vpx, in addition to SAMHD1, overcomes a previously unappreciated restriction for lentiviruses at the level of RT that acts independently of dNTP concentrations and is specific to resting CD4 T cells.

As of 1st June 2020, the US Centres for Disease Control and Prevention reported 104,232 confirmed or probable COVID-19-related deaths in the US. This was more than twice the number of deaths reported in the next most severely impacted country. We jointly model the US epidemic at the state-level, using publicly available death data within a Bayesian hierarchical semi-mechanistic framework. For each state, we estimate the number of individuals that have been infected, the number of individuals that are currently infectious and the time-varying reproduction number (the average number of secondary infections caused by an infected person). We use changes in mobility to capture the impact that non-pharmaceutical interventions and other behaviour changes have on the rate of transmission of SARS-CoV-2. We estimate that R t was only below one in 23 states on 1st June. We also estimate that 3.7% [3.4%–4.0%] of the total population of the US had been infected, with wide variation between states, and approximately 0.01% of the population was infectious. We demonstrate good 3 week model forecasts of deaths with low error and good coverage of our credible intervals. High numbers of COVID-19-related deaths have been reported in the United States, but estimation of the true numbers of infections is challenging. Here, the authors estimate that on 1 June 2020, 3.7% of the US population was infected with SARS-CoV-2, and 0.01% was infectious, with wide variation by state.

Dengue is expanding globally, but how dengue emergence is shaped locally by interactions between climatic and socio-environmental factors is not well understood. Here, we investigate the drivers of dengue incidence and emergence in Vietnam, through analysing 23 years of district-level case data spanning a period of significant socioeconomic change (1998-2020). We show that urban infrastructure factors (sanitation, water supply, long-term urban growth) predict local spatial patterns of dengue incidence, while human mobility is a more influential driver in subtropical northern regions than the endemic south. Temperature is the dominant factor shaping dengue’s distribution and dynamics, and using long-term reanalysis temperature data we show that warming since 1950 has expanded transmission risk throughout Vietnam, and most strongly in current dengue emergence hotspots (e.g., southern central regions, Ha Noi). In contrast, effects of hydrometeorology are complex, multi-scalar and dependent on local context: risk increases under either short-term precipitation excess or long-term drought, but improvements in water supply mitigate drought-associated risks except under extreme conditions. Our findings challenge the assumption that dengue is an urban disease, instead suggesting that incidence peaks in transitional landscapes with intermediate infrastructure provision, and provide evidence that interactions between recent climate change and mobility are contributing to dengue’s expansion throughout Vietnam. The geographic distribution of dengue has been expanding in recent decades, and Vietnam is one of the most severely affected countries. In this study, the authors use Bayesian hierarchical modelling to investigate the socio-environmental and climatic drivers of dengue incidence in Vietnam and how they vary across the country.