The effect of acute acid exposure on immunomodulatory protein secretion, cell survival, and cell cycle progression in tumour cell lines.

Cancer develops when multiple systems fail to suppress uncontrolled cell proliferation. Breast cancers and oesophageal squamous cell carcinoma (OSCC) are common cancers prone to genetic instability. They typically occur in acidic microenvironments which impacts on cell proliferation, apoptosis, and their influence on surrounding cells to support tumour growth and immune evasion. This study aimed to evaluate the impact of the acidic tumour microenvironment on the production of pro-tumorigenic and immunomodulatory factors in cancer cell lines. Multiple factors that may mediate immune evasion were secreted including IL-6, IL-8, G-CSF, IP-10, GDF-15, Lipocalin-2, sICAM-1, and myoglobin. Others, such as VEGF, FGF, and EGF that are essential for tumour cell survival were also detected. Treatment with moderate acidity did not significantly affect secretion of most proteins, whereas very low pH did. Distinct differences in apoptosis were noted between the cell lines, with WHCO6 being better adapted to survive at moderate acid levels. Conditioned medium from acid-treated cells stimulated increased cell viability and proliferation in WHCO6, but increased cell death in MCF-7. This study highlights the importance of acidic tumour microenvironment in controlling apoptosis, cell proliferation, and immune evasion which may be different at different anatomical sites. Immunomodulatory molecules and growth factors provide therapeutic targets to improve the prognosis of individuals with cancer.

Range-wide sources of variation in reproductive rates of northern spotted owls.

We conducted a range-wide investigation of the dynamics of site-level reproductive rate of northern spotted owls using survey data from 11 study areas across the subspecies geographic range collected during 1993-2018. Our analytical approach accounted for imperfect detection of owl pairs and misclassification of successful reproduction (i.e., at least one young fledged) and contributed further insights into northern spotted owl population ecology and dynamics. Both nondetection and state misclassification were important, especially because factors affecting these sources of error also affected focal ecological parameters. Annual probabilities of site occupancy were greatest at sites with successful reproduction in the previous year and lowest for sites not occupied by a pair in the previous year. Site-specific occupancy transition probabilities declined over time and were negatively affected by barred owl presence. Overall, the site-specific probability of successful reproduction showed substantial year-to-year fluctuations and was similar for occupied sites that did or did not experience successful reproduction the previous year. Site-specific probabilities for successful reproduction were very small for sites that were unoccupied the previous year. Barred owl presence negatively affected the probability of successful reproduction by northern spotted owls in Washington and California, as predicted, but the effect in Oregon was mixed. The proportions of sites occupied by northern spotted owl pairs showed steep, near-monotonic declines over the study period, with all study areas showing the lowest observed levels of occupancy to date. If trends continue it is likely that northern spotted owls will become extirpated throughout large portions of their range in the coming decades.

Distance as a barrier to HIV testing among sexual and gender minority populations in the rural southern US: a cross-sectional study.

INTRODUCTION: Sexual and gender minority people who live in rural areas are less likely to have had a HIV test in the previous 12 months compared with those who live in non-rural areas. We assessed the independent contribution of distance and time required to travel to receive a HIV test on recent uptake of HIV testing. METHODS: We conducted a cross-sectional survey of sexual and gender minority populations in the southern US. We used Poisson regression with robust standard errors to estimate prevalence ratios to compare uptake of HIV testing in the previous 12 months among those who traveled more than 20 miles (~32 km) and more than 30 minutes to their most recent HIV test compared with those who traveled less distance and time to their most recent test, respectively. RESULTS: A total of 508 (n=155 rural, n=348 non-rural) participants completed the survey. Of these, 398 (78.5%) had received a HIV test in the previous 12 months. Those who traveled more than 20 miles (~32 km) to their most recent test were more likely to have not received a HIV test in the previous 12 months compared with those who traveled 20 miles (~32 km) or less (adjusted prevalence ratio 2.25; 95% confidence interval 1.22-4.17). There were no differences based on travel time to the most recent test. CONCLUSION: Distance, but not time, to travel to receive a HIV test is independently associated with reduced HIV testing. More geographically proximal options or access to home-based testing might reduce this barrier.

Thermal plasma activation and UV/H2O2 oxidative degradation of pharmaceutical residues.

The aquatic environment becomes increasingly contaminated by anthropogenic pollutants such as pharmaceutical residues. Due to poor biodegradation and continuous discharge of persistent compounds in sewage water samples, pharmaceutical residues might end up in surface waters when not removed. To minimize this pollution, onsite wastewater treatment techniques might complement conventional waste water treatment plants (WWTPs). Advanced oxidation processes are useful techniques, since reactive oxygen species (ROS) are used for the degradation of unwanted medicine residues. In this paper we have studied the advanced oxidation in a controlled laboratory setting using thermal plasma and UV/H2O2 treatment. Five different matrices, Milli-Q water, tap water, synthetic urine, diluted urine and synthetic sewage water were spiked with 14 pharmaceuticals with a concentration of 5 µg/L. All compounds were reduced or completely decomposed by both 150 W thermal plasma and UV/H2O2 treatment. Additionally, also hospital sewage water was tested. First the concentrations of 10 pharmaceutical residues were determined by liquid chromatography mass spectrometry (LC-MS/MS). The pharmaceutical concentration ranged from 0.08 up to 2400 µg/L. With the application of 150 W thermal plasma or UV/H2O2, it was found that overall pharmaceutical degradation in hospital sewage water were nearly equivalent to the results obtained in the synthetic sewage water. However, based on the chemical abatement kinetics it was demonstrated that the degree of degradation decreases with increasing matrix complexity. Since reactive oxygen and nitrogen species (RONS) are continuously produced, thermal plasma treatment has the advantage over UV/H2O2 treatment.

Rhinovirus Detection in the Nasopharynx of Children Undergoing Cardiac Surgery Is Not Associated With Longer PICU Length of Stay: Results of the Impact of Rhinovirus Infection After Cardiac Surgery in Kids (RISK) Study.

OBJECTIVES: To determine whether children with asymptomatic carriage of rhinovirus in the nasopharynx before elective cardiac surgery have an increased risk of prolonged PICU length of stay. STUDY DESIGN: Prospective, single-center, blinded observational cohort study. SETTING: PICU in a tertiary hospital in The Netherlands. PATIENTS: Children under 12 years old undergoing elective cardiac surgery were enrolled in the study after informed consent of the parents/guardians. INTERVENTIONS: The parents/guardians filled out a questionnaire regarding respiratory symptoms. On the day of the operation, a nasopharyngeal swab was obtained. Clinical data were collected during PICU admission, and PICU/hospital length of stay were reported. If a patient was still intubated 3 days after operation, an additional nasopharyngeal swab was collected. Nasopharyngeal swabs were tested for rhinovirus and other respiratory viruses with polymerase chain reaction. MEASUREMENTS AND MAIN RESULTS: Of the 163 included children, 74 (45%) tested rhinovirus positive. Rhinovirus-positive patients did not have a prolonged PICU length of stay (median 2 d each; p = 0.257). Rhinovirus-positive patients had a significantly shorter median hospital length of stay compared with rhinovirus-negative patients (8 vs 9 d, respectively; p = 0.006). Overall, 97 of the patients (60%) tested positive for one or more respiratory virus. Virus-positive patients had significantly shorter PICU and hospital length of stay, ventilatory support, and nonmechanical ventilation. Virus-negative patients had respiratory symptoms suspected for a respiratory infection more often. In 31% of the children, the parents reported mild upper respiratory complaints a day prior to the cardiac surgery, this was associated with postextubation stridor, but no other clinical outcome measures. CONCLUSIONS: Preoperative rhinovirus polymerase chain reaction positivity is not associated with prolonged PICU length of stay. Our findings do not support the use of routine polymerase chain reaction testing for respiratory viruses in asymptomatic children admitted for elective cardiac surgery.

Biventricular function in exercise during autonomic (thoracic epidural) block.

BACKGROUND: Blockade of cardiac sympathetic fibers by thoracic epidural anesthesia (TEA) was previously shown to reduce right and left ventricular systolic function and effective pulmonary arterial elastance. At conditions of constant paced heart rate, cardiac output and systemic hemodynamics were unchanged. In this study, we further investigated the effect of cardiac sympathicolysis during physical stress and increased oxygen demand. METHODS: In a cross-over design, 12 patients scheduled to undergo thoracic surgery performed dynamic ergometric exercise tests with and without TEA. Hemodynamics were monitored and biventricular function was measured by transthoracic two-dimensional and M-mode echocardiography, pulsed wave Doppler and tissue Doppler imaging. RESULTS: TEA attenuated systolic RV function (TV S': - 21%, P < 0.001) and LV function (MV S': - 14%, P = 0.025), but biventricular diastolic function was not affected. HR (- 11%, P < 0.001), SVI (- 15%, P = 0.006), CI (- 21%, P < 0.001) and MAP (- 12%, P < 0.001) were decreased during TEA, but SVR was not affected. Exercise resulted in significant augmentation of systolic and diastolic biventricular function. During exercise HR, SVI, CI and MAP increased (respectively, + 86%, + 19%, + 124% and + 17%, all P < 0.001), whereas SVR decreased (- 49%, P < 0.001). No significant interactions between exercise and TEA were found, except for RPP (P = 0.024) and MV E DT (P = 0.035). CONCLUSION: Cardiac sympathetic blockade by TEA reduced LV and RV systolic function but did not significantly blunt exercise-induced increases in LV and RV function. These data indicate that additional mechanisms besides those controlled by the cardiac sympathetic nervous system are involved in the regulation of cardiac function during dynamic exercise. Trial registration Clinical trial registration: Nederlands Trial Register, NTR 4880 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4880 .

Recontacting non-BRCA1/2 breast cancer patients for germline CHEK2 c.1100del pathogenic variant testing: uptake and patient experiences.

BACKGROUND: CHEK2 has been recognized as a breast cancer risk gene with moderate effect. Women who have previously tested negative for a BRCA1/2 gene germline pathogenic variant may benefit from additional genetic testing for the CHEK2 c.1100del pathogenic variant. The aims of this study were: 1) to assess the uptake of an active approach by recontacting BRCA1/2-negative women for additional CHEK2 c.1100del testing on stored DNA-samples and 2) to explore patients' experiences with this approach. METHODS: Between 2015 and 2017, women who had been tested earlier negative for BRCA1/2 germline pathogenic variants, were recontacted for additional CHEK2 c.1100del testing on stored DNA-samples, free-of-charge. They received an information letter about the CHEK2 pathogenic variant and could return an informed consent form when they opted for additional genetic testing. Those in whom the CHEK2 pathogenic variant was absent, received a letter describing this result. Those who tested positive, were invited for a personal counseling at the department of genetics. On average 21 months (range 4-27) after the genetic test result, a questionnaire was sent to all identified carriers and a control group of women who tested negative for the pathogenic variant to explore patients' experiences with our approach. RESULTS: In total, 70% (N = 1666) of the N = 2377 women contacted opted for additional testing, and 66 (4%) of them proved to be carriers of the CHEK2 c.1100del pathogenic variant. Regardless of the outcome of the genetic test, women were generally satisfied with our approach and reported that the written information was sufficient to make an informed decision about the additional CHEK2 testing. CONCLUSIONS: The uptake (70%) of our approach was considered satisfactory. Patients considered the benefits more important than the psychosocial burden. Given the rapid developments in DNA-diagnostics, our findings may support future initiatives to recontact patients about additional genetic testing when they previously tested negative for a pathogenic variant in a breast cancer gene.

Genetic variants and expression changes in urgency urinary incontinence: A systematic review.

AIM: To perform a systematic review summarizing the knowledge of genetic variants, gene, and protein expression changes in humans and animals associated with urgency urinary incontinence (UUI) and to provide an overview of the known molecular mechanisms related to UUI. METHODS: A systematic search was performed on March 2, 2020, in PubMed, Embase, Web of Science, and the Cochrane library. Retrieved studies were screened for eligibility. The risk of bias was assessed using the ROBINS-I (human) and SYRCLE (animal) tool. Data were presented in a structured manner and in the case of greater than five studies on a homogeneous outcome, a meta-analysis was performed. RESULTS: Altogether, a total of 10,785 records were screened of which 37 studies met the inclusion criteria. Notably, 24/37 studies scored medium-high to high on risk of bias, affecting the value of the included studies. The analysis of 70 unique genes and proteins and three genome-wide association studies showed that specific signal transduction pathways and inflammation are associated with UUI. A meta-analysis on the predictive value of urinary nerve growth factor (NGF) levels showed that increased urinary NGF levels correlate with UUI. CONCLUSION: The collective evidence showed the involvement of two molecular mechanisms (signal transduction and inflammation) and NGF in UUI, enhancing our understanding of the pathophysiology of UUI. Unfortunately, the risk of bias was medium-high to high for most studies and the value of many observations remains unclear. Future studies should focus on elucidating how deficits in the two identified molecular mechanisms contribute to UUI and should avoid bias.

Animal to human translation: a systematic scoping review of reported concordance rates.

BACKGROUND: Drug development is currently hampered by high attrition rates; many developed treatments fail during clinical testing. Part of the attrition may be due to low animal-to-human translational success rates; so-called "translational failure". As far as we know, no systematic overview of published translational success rates exists. SYSTEMATIC SCOPING REVIEW: The following research question was examined: "What is the observed range of the animal-to-human translational success (and failure) rates within the currently available empirical evidence?". We searched PubMed and Embase on 16 October 2017. We included reviews and all other types of "umbrella"-studies of meta-data quantitatively comparing the translational results of studies including at least two species with one being human. We supplemented our database searches with additional strategies. All abstracts and full-text papers were screened by two independent reviewers. Our scoping review comprises 121 references, with various units of measurement: compound or intervention (k = 104), study/experiment (k = 10), and symptom or event (k = 7). Diagnostic statistics corresponded with binary and continuous definitions of successful translation. Binary definitions comprise percentages below twofold error, percentages accurately predicted, and predictive values. Quantitative definitions comprise correlation/regression (r2) and meta-analyses (percentage overlap of 95% confidence intervals). Translational success rates ranged from 0 to 100%. CONCLUSION: The wide range of translational success rates observed in our study might indicate that translational success is unpredictable; i.e. it might be unclear upfront if the results of primary animal studies will contribute to translational knowledge. However, the risk of bias of the included studies was high, and much of the included evidence is old, while newer models have become available. Therefore, the reliability of the cumulative evidence from current papers on this topic is insufficient. Further in-depth "umbrella"-studies of translational success rates are still warranted. These are needed to evaluate the probabilistic evidence for predictivity of animal studies for the human situation more reliably, and to determine which factors affect this process.

Bacillus subtilis Strain DSM 29784 Modulates the Cecal Microbiome, Concentration of Short-Chain Fatty Acids, and Apparent Retention of Dietary Components in Shaver White Chickens during Grower, Developer, and Laying Phases.

This study investigated the efficacy of a single strain of Bacillus subtilis (SSB) in modulating the composition of cecal microbiota and its link to the concentration of short-chain fatty acids (SCFA) and apparent retention (AR) of components. A total of 720, 4-week-old Shaver White chicks were allotted to control (CON), 1.1E+08 (low, LSSB), 2.2E+08 (medium, MSSB), or 1.1E+09 (high, HSSB) CFU/kg of diet groups. At grower (10-week), developer (16-week), and laying (28-week) phases, excreta and cecal digesta samples were taken for AR, microbial, and SCFA analyses. Microbial analysis involved high-throughput sequencing of the V3-V4 hypervariable regions of 16S rRNA gene. Bacterial diversity decreased (P < 0.05) at the developer phase as the SSB dose increased; however, a distinct clustering pattern (P < 0.05) of bacterial community was noted. Bacteroides and Faecalibacterium were differentially enriched in the developer for SSB-fed compared to CON-fed birds. Although no differences in microbial diversity were detected in grower and layer phases, different species of Clostridium (XVIII, XIVa, IV, and XIVb)-major butyrate producers-were identified in all phases, with stronger effect sizes for SSB-fed compared to CON-fed birds. Isobutyric acid was elevated in dose response (P = 0.034) in layer phase. In addition, the relative abundances of Alistipes, Lactobacillus, and Bifidobacterium were positively correlated (P < 0.05), with AR of most components for SSB-fed birds in the pullet phase. The results suggested that supplementing chickens' diet with B. subtilis DSM 29784 may selectively enrich beneficial bacterial communities, which in turn are critical in promoting the growth and performance of hens.IMPORTANCE In egg-laying chickens, the trend in the move away from the cage to alternative housing systems and restriction in antimicrobial use requires alternative approaches to maintain health and prevent diseases. There is increased research and commercial interest toward alternative gut health solutions while improving the performance and product safety in poultry production systems. One such approach, in recognition of the importance of the gut microbial community, is the use of microbes as feed supplements (such as probiotics). Unlike meat-type chickens, studies assessing the efficacy of such microbial supplements are limited for egg-laying chickens. Thus, by conducting a comprehensive assessment of the hen microbiota in response to various levels of B. subtilis DSM 29784 during the pullet phase (grower and developer) and the layer phase, the present study demonstrates the importance of direct-fed microbes in modulating gut microbiome, which may relate to improved performance efficiency in the pullet and layer phases.

The past and future roles of competition and habitat in the range-wide occupancy dynamics of Northern Spotted Owls.

Slow ecological processes challenge conservation. Short-term variability can obscure the importance of slower processes that may ultimately determine the state of a system. Furthermore, management actions with slow responses can be hard to justify. One response to slow processes is to explicitly concentrate analysis on state dynamics. Here, we focus on identifying drivers of Northern Spotted Owl (Strix occidentalis caurina) territorial occupancy dynamics across 11 study areas spanning their geographic range and forecasting response to potential management actions. Competition with Barred Owls (Strix varia) has increased Spotted Owl territory extinction probabilities across all study areas and driven recent declines in Spotted Owl populations. Without management intervention, the Northern Spotted Owl subspecies will be extirpated from parts of its current range within decades. In the short term, Barred Owl removal can be effective. Over longer time spans, however, maintaining or improving habitat conditions can help promote the persistence of northern spotted owl populations. In most study areas, habitat effects on expected Northern Spotted Owl territorial occupancy are actually greater than the effects of competition from Barred Owls. This study suggests how intensive management actions (removal of a competitor) with rapid results can complement a slower management action (i.e., promoting forest succession).

The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium.

BACKGROUND: We previously showed that the BRCA1 variant c.5096G>A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1*R1699Q carriers. METHODS: Data were collected from 129 BRCA1*R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions. RESULTS: In this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83). CONCLUSION: Our results confirm that BRCA1*R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history.

Process Evaluation of Nurse-Led Online Self-Management Support for Family Caregivers to Deal With Behavior Changes of a Relative With Dementia (Part 1): Mixed Methods Study.

BACKGROUND: Coping with behavioral changes is a daily challenge for family caregivers in all phases of dementia, and assistance is needed for it. An online self-management support intervention was therefore developed and conducted involving the following elements: (1) email contact with a specialized dementia nurse, (2) online videos, and (3) e-bulletins containing information about behavior changes and how to manage them. OBJECTIVE: The aim of this study was to understand (1) family caregivers' actual use of various elements of the online self-management support, (2) family caregivers' evaluation and satisfaction with the various elements, and (3) nurses' usage and evaluations of the online support through the tailored email contacts. METHODS: A mixed methods design was used in this process evaluation, combining quantitative and qualitative methods including analyses of dementia nurses' registration forms, the number of clicks on online videos and e-bulletins, evaluation questions answered by family caregivers in a survey questionnaire, semistructured interviews with family caregivers and nurses, and analysis of the content of the email contacts. RESULTS: The actual use of various elements of the online self-management support by family caregivers varied: 78% (21/27) of family caregivers had an email contact with the specialist nurse, 80% (43/54) of family caregivers clicked on an online video, and 37% (30/81) clicked on an e-bulletin. Family caregivers showed positive evaluations and satisfaction. The tailor-made approach in the personal email contacts in particular was valued by the family caregivers. Nurses' evaluations about providing self-management support online were mixed as it was a relatively new task for them. CONCLUSIONS: An important insight is that not all participants made optimum use of the various elements of the intervention. Nurses also said that the email contacts were more often used to express feelings about coping with behavioral changes. More research is needed to investigate the reasons why people accept, adopt, and adhere to online interventions to reduce cases where they are not used and to back them up appropriately with tailored (online) information and advice for their personal situations.

Sleep and Microdialysis: An Experiment and a Systematic Review of Histamine and Several Amino Acids.

Sleep seems essential to proper functioning of the prefrontal cortex (PFC). The role of different neurotransmitters has been studied, mainly the catecholamines and serotonin. Less attention has been paid to the amino acid transmitters and histamine. Here, we focus on the activity of these molecules in the PFC during sleep and sleep deprivation (SD). We determined extracellular concentrations of histamine and 8 amino acids in the medial PFC before, during and after SD. Additionally, we systematically reviewed the literature on studies reporting microdialysis measurements relating to sleep throughout the brain. In our experiment, median concentrations of glutamate were higher during SD than during baseline (p = 0.013) and higher during the dark-active than during the resting phase (p = 0.003). Glutamine was higher during post-SD recovery than during baseline (p = 0.010). For other compounds, no differences were observed between light and dark circadian phase, and between sleep deprivation, recovery and baseline. We retrieved 13 papers reporting on one or more of the molecules of interest during naturally occurring sleep, 2 during sleep deprivation and 2 during both. Only two studies targeted PFC. Histamine was low during sleep, but high during sleep deprivation and wakefulness, irrespective of brain area. Glu (k = 11) and GABA (k = 8) concentrations in different brain areas were reported to peak during sleep or wakefulness or to lack state-dependency. Aspartate, glycine, asparagine and taurine were less often studied (1-2 times), but peaked exclusively during sleep. Sleep deprivation increased glutamate and GABA exclusively in the cortex. Further studies are needed for drawing solid conclusions.

Rural primary care providers' attitudes towards sexual and gender minorities in a midwestern state in the USA.

INTRODUCTION: Lesbian, gay, bisexual, and transgender (LGBT) individuals experience poorer health outcomes compared to their heterosexual and cisgender counterparts. Rural residents might be particularly vulnerable due to their geographic isolation and residence in a setting that potentially holds more conservative norms. Data on the attitudes of rural providers in the USA towards this community are currently limited. The purpose of this study was to describe existing attitudes of primary care providers in rural Michigan towards each LGBT subpopulation, and to identify independent correlates of these attitudes. METHODS: From May to July 2017, a modified Dillman mail-out method was used to collect data from 113 rural primary care providers. The non-incentivized paper-based survey included five validated Attitudes Toward LGBT People scales to assess feelings, thoughts, and predicted behaviors towards gay men, lesbian women, bisexual men, bisexual women, and transgender persons. Kruskal-Wallis tests were performed to assess global differences in the attitude scores for each subpopulation across strata of demographic characteristics and past clinical experiences. Multivariable linear regression models were formulated to identify independent correlates of attitudes towards each subpopulation. RESULTS: Age range was 25-73 years (mean=49 years), and the majority were non-Hispanic white (92.92%), and female (71.68%). More than three-quarters indicated being religious, with varying extents (80.53%). Approximately half (54.87%) received education specific to LGBT health during their professional degree program, and most (88.50%) believed it should be required. Generally favorable attitudes were noted towards each LGBT subpopulation. Increasing levels of religiosity were associated with less favorable attitudes, whereas having received education specific to LGBT health and believing it should be required were associated with more favorable attitudes. CONCLUSION: Improving attitudes of rural providers towards LGBT individuals may positively influence the provision of high-quality health care. Ensuring the delivery of culturally competent services will require multi-level systemic changes. Ongoing trainings and novel interventions to enhance provider education and cultural competence could prove beneficial.

Intracerebral microdialysis of adenosine and adenosine monophosphate - a systematic review and meta-regression analysis of baseline concentrations.

Microdialysis is a method to study the extracellular space in vivo, based on the principle of diffusion. It can be used to measure various small molecules including the neuroregulator adenosine. Baseline levels of the compounds measured with microdialysis vary over studies. We systematically reviewed the literature to investigate the full range of reported baseline concentrations of adenosine and adenosine monophosphate in microdialysates. We performed a meta-regression analysis to study the influence of flow rate, probe membrane surface area, species, brain area and anaesthesia versus freely behaving, on the adenosine concentration. Baseline adenosine concentrations in microdialysates ranged from 0.8 to 2100 nM. There was limited evidence on baseline adenosine monophosphate concentrations in microdialysates. Across studies, we found effects of flow rate and anaesthesia versus freely behaving on dialysate adenosine concentrations (p ≤ 0.001), but not of probe membrane surface, species, or brain area (p ≥ 0.14). With increasing flow rate, adenosine concentrations decreased. With anaesthesia, adenosine concentrations increased. The effect of other predictor variables on baseline adenosine concentrations, for example, post-surgical recovery time, could not be analysed because of a lack of reported data. This study shows that meta-regression can be used as an alternative to new animal experiments to answer research questions in the field of neurochemistry. However, current levels of reporting of primary studies are insufficient to reach the full potential of this approach; 63 out of 133 studies could not be included in the analysis because of insufficient reporting, and several potentially relevant factors had to be excluded from the analyses. The level of reporting of experimental detail needs to improve.

Respiratory Viruses in Invasively Ventilated Critically Ill Patients-A Prospective Multicenter Observational Study.

OBJECTIVES: The presence of respiratory viruses and the association with outcomes were assessed in invasively ventilated ICU patients, stratified by admission diagnosis. DESIGN: Prospective observational study. SETTING: Five ICUs in the Netherlands. PATIENTS: Between September 1, 2013, and April 30, 2014, 1,407 acutely admitted and invasively ventilated patients were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Nasopharyngeal swabs and tracheobronchial aspirates were collected upon intubation and tested for 14 respiratory viruses. Out of 1,407 patients, 156 were admitted because of a severe acute respiratory infection and 1,251 for other reasons (non-severe acute respiratory infection). Respiratory viruses were detected in 28.8% of severe acute respiratory infection patients and 17.0% in non-severe acute respiratory infection (p < 0.001). In one third, viruses were exclusively detected in tracheobronchial aspirates. Rhinovirus and human metapneumovirus were more prevalent in severe acute respiratory infection patients (9.6% and 2.6% vs 4.5 and 0.2%; p = 0.006 and p < 0.001). In both groups, there were no associations between the presence of viruses and the number of ICU-free days at day 28, crude mortality, and mortality in multivariate regression analyses. CONCLUSIONS: Respiratory viruses are frequently detected in acutely admitted and invasively ventilated patients. Rhinovirus and human metapneumovirus are more frequently found in severe acute respiratory infection patients. Detection of respiratory viruses is not associated with worse clinically relevant outcomes in the studied cohort of patients.

Person-fit feedback on inconsistent symptom reports in clinical depression care.

BACKGROUND: Depressive patients can present with complex and different symptom patterns in clinical care. Of these, some may report patterns that are inconsistent with typical patterns of depressive symptoms. This study aimed to evaluate the validity of person-fit statistics to identify inconsistent symptom reports and to assess the clinical usefulness of providing clinicians with person-fit score feedback during depression assessment. METHODS: Inconsistent symptom reports on the Inventory of Depressive Symptomatology Self-Report (IDS-SR) were investigated quantitatively with person-fit statistics for both intake and follow-up measurements in the Groningen University Center of Psychiatry (n = 2036). Subsequently, to investigate the causes and clinical usefulness of on-the-fly person-fit alerts, qualitative follow-up assessments were conducted with three psychiatrists about 20 of their patients that were randomly selected. RESULTS: Inconsistent symptom reports at intake (12.3%) were predominantly characterized by reporting of severe symptoms (e.g. psychomotor slowing) without mild symptoms (e.g. irritability). Person-fit scores at intake and follow-up were positively correlated (r = 0.45). Qualitative interviews with psychiatrists resulted in an explanation for the inconsistent response behavior (e.g. complex comorbidity, somatic complaints, and neurological abnormalities) for 19 of 20 patients. Psychiatrists indicated that if provided directly after the assessment, a person-fit alert would have led to new insights in 60%, and be reason for discussion with the patient in 75% of the cases. CONCLUSIONS: Providing clinicians with automated feedback when inconsistent symptom reports occur is informative and can be used to support clinical decision-making.

Effect of a Low vs Intermediate Tidal Volume Strategy on Ventilator-Free Days in Intensive Care Unit Patients Without ARDS: A Randomized Clinical Trial.

Importance: It remains uncertain whether invasive ventilation should use low tidal volumes in critically ill patients without acute respiratory distress syndrome (ARDS). Objective: To determine whether a low tidal volume ventilation strategy is more effective than an intermediate tidal volume strategy. Design, Setting, and Participants: A randomized clinical trial, conducted from September 1, 2014, through August 20, 2017, including patients without ARDS expected to not be extubated within 24 hours after start of ventilation from 6 intensive care units in the Netherlands. Interventions: Invasive ventilation using low tidal volumes (n = 477) or intermediate tidal volumes (n = 484). Main Outcomes and Measures: The primary outcome was the number of ventilator-free days and alive at day 28. Secondary outcomes included length of ICU and hospital stay; ICU, hospital, and 28- and 90-day mortality; and development of ARDS, pneumonia, severe atelectasis, or pneumothorax. Results: In total, 961 patients (65% male), with a median age of 68 years (interquartile range [IQR], 59-76), were enrolled. At day 28, 475 patients in the low tidal volume group had a median of 21 ventilator-free days (IQR, 0-26), and 480 patients in the intermediate tidal volume group had a median of 21 ventilator-free days (IQR, 0-26) (mean difference, -0.27 [95% CI, -1.74 to 1.19]; P = .71). There was no significant difference in ICU (median, 6 vs 6 days; 0.39 [-1.09 to 1.89]; P = .58) and hospital (median, 14 vs 15 days; -0.60 [-3.52 to 2.31]; P = .68) length of stay or 28-day (34.9% vs 32.1%; hazard ratio [HR], 1.12 [0.90 to 1.40]; P = .30) and 90-day (39.1% vs 37.8%; HR, 1.07 [0.87 to 1.31]; P = .54) mortality. There was no significant difference in the percentage of patients developing the following adverse events: ARDS (3.8% vs 5.0%; risk ratio [RR], 0.86 [0.59 to 1.24]; P = .38), pneumonia (4.2% vs 3.7%; RR, 1.07 [0.78 to 1.47]; P = .67), severe atelectasis (11.4% vs 11.2%; RR, 1.00 [0.81 to 1.23]; P = .94), and pneumothorax (1.8% vs 1.3%; RR, 1.16 [0.73 to 1.84]; P = .55). Conclusions and Relevance: In patients in the ICU without ARDS who were expected not to be extubated within 24 hours of randomization, a low tidal volume strategy did not result in a greater number of ventilator-free days than an intermediate tidal volume strategy. Trial Registration: ClinicalTrials.gov Identifier: NCT02153294.